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Neuromodulation: Purinergic Signaling in Respiratory Control

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Abstract

The main functions of the respiratory neural network are to produce a coordinated, efficient, rhythmic motor behavior and maintain homeostatic control over blood oxygen and CO2/pH levels. Purinergic (ATP) signaling features prominently in these homeostatic reflexes. The signaling actions of ATP are produced through its binding to a diversity of ionotropic P2X and metabotropic P2Y receptors. However, its net effect on neuronal and network excitability is determined by the interaction between the three limbs of a complex system comprising the signaling actions of ATP at P2Rs, the distribution of multiple ectonucleotidases that differentially metabolize ATP into ADP, AMP, and adenosine (ADO), and the signaling actions of ATP metabolites, especially ADP at P2YRs and ADO at P1Rs. Understanding the significance of purinergic signaling is further complicated by the fact that neurons, glia, and the vasculature differentially express P2 and P1Rs, and that both neurons and glia release ATP. This article reviews at cellular, synaptic, and network levels, current understanding and emerging concepts about the diverse roles played by this three‐part signaling system in: mediating the chemosensitivity of respiratory networks to hypoxia and CO2/pH; modulating the activity of rhythm generating networks and inspiratory motoneurons, and; controlling blood flow through the cerebral vasculature. © 2013 American Physiological Society. Compr Physiol 3:331‐363, 2013.

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Figure 1. Figure 1.

When ATP is released into the extracellular space, it acts via a three‐part signaling system comprising: (i) the actions of ATP (and ADP) at P2Rs; (ii) diverse ecto‐nucleotidases with differential substrate affinities that degrade ATP and its byproducts ultimately to adenosine (ADO); and, (iii) the actions of ADO at P1Rs. (Ecto 5′, ecto‐5′‐ectonucleotidase; ENPPs, ectonucleotide pyrophosphatase/phosphodiesterease; TNAP, tissue nonspecific alkaline phosphatase).

Figure 2. Figure 2.

Purinergic signaling has multiple roles in shaping the biphasic ventilatory response to hypoxia. (A) The hypoxic ventilatory response, shown here from anesthetized piglets (green) and adult pigs (blue) exposed to 6% inspired O2, is biphasic. It comprises an initial increase followed by a gradual decline, referred to as the secondary depression or “roll‐off.” Note that despite a similar initial increase (upward arrows), compare to adults (blue downward arrow), the roll‐off is more pronounced in neonates (green downward arrow) where ventilation falls below baseline (green shading) [Adapted, with permission, from reference ()]. (B) In the carotid body, the P2X2 receptor subunit is a major contributor to the initial increase in ventilation that is evoked by hypoxia in mice. The graph shows respiratory responses (plotted as change in minute ventilation (E) from control) to varying levels of hypoxia in conscious wild‐type (blue) and P2X2‐deficient (green) mice. Adapted, with permission, from reference (). (C and D) ATP released within the ventral respiratory column during hypoxia offsets the magnitude of the secondary respiratory depression. Traces in (C) illustrate changes in the arterial blood pressure (ABP), integrated phrenic nerve discharge (∫Phrenic), and null and ATP sensor currents (measured at the ventral medullary surface immediately ventral to the ventral respiratory column) during exposure to systemic hypoxia (10% O2 in the inspired air). Prior to hypoxia, rats were mechanically hyperventilated to induce central apnea (arterial PCO2 and end‐tidal CO2 below apneic threshold). Note that the release of ATP at the ventral surface of the medulla oblongata occurs after the initial increase in phrenic nerve activity. (D) P2 receptor blockade in the ventrolateral medulla augments the hypoxia‐induced secondary depression of ventilation in adult rats. Summary data show the effect of pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS, P2 receptor antagonist) on changes in minute ventilation evoked by hypoxia. *Significant difference from control response, P < 0.05. Adapted, with permission, from reference (). (E) During hypoxia, adenosine (ADO) contributes to the secondary depression of ventilation. Curves illustrate ventilatory responses of decerebrate rabbit pups to 6% O2 during saline infusion (control) or following infusion of ADO antagonists (aminophylline, 25 mg kg−1; or 8‐p‐sulfophenyltheophylline, 5 mg kg−1). Ventilation is expressed as percent of the prehypoxic level (% control). Adapted, with permission, from reference ().

Figure 3. Figure 3.

Carotid body chemoreceptor function: location, purinergic signaling mechanisms and central projections. (A) The carotid bodies are located bilaterally in the neck at the bifurcation of the common carotid artery into the internal and external carotid arteries. (B) Enlarged view of the box in (A) showing the carotid body and its afferent innervation via the carotid sinus nerve. (C) Enlarged view of a cross‐section through the carotid body (at the blue line in B) showing arrangement of glomus cells (Type I cells; the sensors), sustentacular cells (Type II cells; glia‐like), capillaries and carotid sinus nerve and parasympathetic nerve endings (efferent axon). Signal transducation pathways for conversion of decreased O2 (lower Glomus cell [steps 1‐8]) increased CO2 (upper Glomus cell [steps i‐vii + 8]) and into transmitter release and action potential generation in carotid sinus nerve are depicted. Autocrine (step I) and paracrine (step II) actions of ATP and ADO (step 8) are also depicted. (D) Dorsal view of the medulla and pons showing central projections of carotid sinus nerve afferent fibers in the medulla. The first‐order excitatory synapse is in the nucleus tractus solitarius (NTS). These neurons project to the pontine respiratory group (PRG) and chemosensitive neurons in the parafacial respiratory group/retrofacial nucleus (pFRG/RTN) that in turn send excitatory projections to the pre‐BötC and possibly other regions of the ventral respiratory column. Note that while this diagram focuses on purinergic signaling in the carotid body, additional small molecule neurotransmitters and neuromodulators contribute to chemosensory processing in the rat carotid body.

Figure 4. Figure 4.

Proposed model of the three‐part ATP signaling system operating at the tripartite, glutamatergic inspiratory synapse (comprising pre‐ and postsynaptic neurons and astrocytes) in the ventral respiratory column and pre‐BötC. A volley of action potentials in presynaptic neuron during inspiration evokes glutamate (Glu) release (), which excites the postsynaptic neuron via ionotropic (GluR) and metabotropic (mGluR) glutamate receptors. When ATP is released into the extracellular space (), it directly activates P2Y1Rs on neurons () and glia (). In glia, ATP evokes an increase in Ca2+ () (via mechanisms outlined in Figure ), which leads to the exocytotic release of gliotransmitters ATP, glutamate (Glu) (), and D‐serine (not shown). Glu indirectly excites the postsynaptic neuron through ionotropic (AMPA and NMDAR) or mGluRs () while ATP acts via P2Rs that couple through phospholipase C and protein kinase C (PKC) and modulate membrane ion channels (see Figure ). ATP also acts in autocrine/paracrine manner to enhance gliotransmitter release (). ATP is degraded by ectonucleotidases (), producing ADP (which activates P2Y1Rs, not shown) and adenosine (ADO), which acts on presynaptic P1Rs to inhibit Glu release () and postsynaptic P1Rs (), causing hyperpolarization via activation of KATP channels.

Figure 5. Figure 5.

The pre‐BötC and pre‐BötC respiratory neurons are sensitive to ATP. (A) Rhythmic XII nerve activity recorded from a rat medullary slice preparation showing a dramatic increase in burst frequency following local injection of ATP (100 μM, 10 s) or the nonhydrolyzable ATP analogue, ATPγS (100 μM, 10 s) into the pre‐BötC. (B) Current‐clamp recording from a respiratory neuron displaying voltage‐dependent bursting behavior. In the top trace of membrane potential (VM), bursts occur at the same frequency as the XII nerve (∫XII). Spontaneous burst frequency increases when cell is depolarized from −65 to −60 and −55 mV. C. This neuron responded to local application of the P2YR agonist, 2MeSADP (1 mM), with an inward current (IM = membrane current) or depolarization. (D) Whole‐cell recording from a nonpacemaker respiratory neuron that responds to ATP and 2MeSADP with an inward current or depolarization. (A) Adapted, with permission, from reference () (B‐D) from reference ()).

Figure 6. Figure 6.

Glia contribute to the increase in inspiratory‐related frequency evoked by ATP in the pre‐BötC in vitro. Rhythmic inspiratory‐related activity recorded as integrated XII nerve activity (∫XII) from a rat medullary slice illustrates frequency increases evoked by local application of ATP (0.1 mM, 10 s, A) and SP (1 μM, 10 s, B) into the pre‐BötC during control conditions (left panels) and after disruption of rhythm by bath application (1‐2 h) of the glial toxin [methionine sulfoxamine (MSO, 0.1 mM)] and the subsequent restoration of rhythm by bath application of glutamine (GLN, 1.5 mM, middle panels] (n = 7). (*Significant difference between ATP responses, P < 0.001. Adapted, with permission, from reference ().

Figure 7. Figure 7.

Signaling cascades through which ATP is hypothesized to affect astrocytes and subsequently neuronal excitability. Extracellular ATP activates astrocytic P2Y, including P2Y1, receptors (), activating the Gαq/11 second messenger cascade () which acts through PLC, PIP2 and IP3 () to evoke the release of Ca2+ from intracellular stores (). Increased Ca2+ triggers exocytotic release of ATP, glutamate, and D‐serine (). Astrocytic ATP can act in an autocrine/paracrine manner on other astrocytes to evoke further transmitter release (ATP‐evoked ATP release) and propagate Ca2+ waves through local glial networks (). ATP is also hypothesized to excite local neurons, in part via P2Y1Rs () and the Gαq/11 second messenger pathway (), which, via activation of PKC (), modulates membrane ion channels including ICAN () to increase excitability. Astrocytic glutamate will act in an autocrine/ paracrine manner on astrocytes via mGluRs (not shown) and increase neuronal excitability through activation of glutamate receptors (mGluRs, AMPA, NMDA) (). Astrocytic D‐serine, a positive allosteric modulator of the NMDA subtype of glutamate receptor, may also increase excitability by potentiating NMDA currents (). Abbreviations: DAG, diacyl‐glycerol; ER, endoplasmic reticulum; Glu, glutamate; IP3, inositol trisphosposphate; mGluR, metabotropic glutamate receptor; PIP2, phosphatidylinositol 4,5‐bisphosphate; PKC, protein kinase C; PLC, phospholipase C; R, receptor).

Figure 8. Figure 8.

Local application of ATP into the pre‐BötC evokes a frequency response that closely follows the ATP concentration profile. (A) Schematic of the experimental setup showing the rhythmic medullary slice, triple‐barrel drug pipette for pressure injecting drugs (ATP) and the ATP and null sensors, all placed within the pre‐BötC. ATP (100 μ, 10 s) is injected into the pre‐BötC (site 1) and the ATP concentration within the pre‐BotC (difference current between null and ATP sensor currents) and inspiratory frequency are monitored (recorded from the XII nerve via a suction electrode). The drug injection pipette is then moved away from the pre‐BötC to site 2 (140 μm from site 1). (B) Trace of integrated XII nerve activity (∫XII) showing the rapid frequency response evoked by ATP in site 1. (C) Plots showing (for the same medullary slice preparation shown in B) the effects of locally applying ATP within the pre‐BötC (starting at t = 0) on inspiratory frequency (blue trace) and the ATP difference current (ATP sensor current‐null sensor current) within the pre‐BötC (green). (D) Inspiratory frequency and ATP difference current recorded in response to locally applying ATP at site 2. This more distant injection produces a different ATP concentration profile within the pre‐BötC, and, importantly, the frequency response still follows the ATP concentration profile measured within the pre‐BötC. Adapted, with permission, from reference ().

Figure 9. Figure 9.

Differential purinergic modulation of pre‐BötC rhythm in rhythmic medullary slice preparations from mouse and rat. (A) P2Y1R activation in the pre‐BötC increases frequency in mouse and rat. Integrated XII nerve (∫XII) recordings showing responses to local application of the P2Y1R agonist MRS 2365 (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (B) Differential effects of ATP on pre‐BötC rhythm in mouse and rat. ∫XII recordings showing responses to local application of and ATP (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (C) DPCPX (an A1 ADOR antagonist) in the pre‐BötC of mouse unmasks an ATP‐mediated frequency increase. ∫XII recordings showing responses to local application of ATP (0.1 mM, 10 s; left trace) under control conditions and after a 90 s preapplication of an A1R antagonist (2 μM DPCPX; right trace). (D) Real‐time polymerase chain reaction analysis reveals differential expression of ectonucleotidase isoforms in tissue punches from mouse and rat. The percentage contribution of each ectonucleotidase isoform to the total ectonucleotidase mRNA expressed in pre‐BötC punches from rat (n = 4) and mouse (n = 6). Error bars indicate SEM. co.# indicates copy number. *Significant difference between the compared columns. Adapted, with permission, from reference ().

Figure 10. Figure 10.

ATP released at the ventral medullary surface contributes to the hypercapnic ventilatory response via a P2R mechanism. (A) Rapid CO2‐induced release of ATP from the ventral surface of the medulla. An increase in the level of inspired CO2 in an adult anesthetized rat that had been hyperventilated to depress respiratory activity. Traces show changes in ATP and null sensor currents, respiratory activity (integrated phrenic nerve discharge, ∫phrenic) and respiratory frequency (fR) and end‐tidal CO2. The “Net ATP” trace represents the difference in signal between ATP and null sensors. (B) Expanded portion of A illustrating that ATP release precedes (arrow) respiratory activation. (C) Placement of sensors on the ventral surface of the medulla (py, pyramidal tract). The sensor surface is the entire platinum wire in contact with the ventral surface. Subsequent studies used small circular sensors to define ATP release sites along the ventral medullary surface (). (D) ATP receptor blockade on the chemosensitive areas of the ventral medullary surface attenuates the effect of CO2 on breathing in rats. Sequential recordings illustrating the effect of increasing concentrations of the P2 antagonist pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS) on the threshold level of end‐tidal CO2 level required to induce respiratory activity from hypocapnic apnoea. (E) Summary data (mean ± standard error) showing the increase in threshold levels of end‐tidal CO2 required to induce breathing from apnoea in the presence of PPADS (white columns; n = 8) or TNP‐ATP (black columns; n = 7) on the ventral medullary surface. * indicates significant difference, P < 0.05. Adapted, with permission, from reference ().

Figure 11. Figure 11.

Optogenetic stimulation of channel Rhodopsin 2‐expressing astrocytes on the ventral medullary surface activated phox2b positive chemoreceptor neurons via an ATP‐dependent mechanism and triggered robust respiratory responses in vivo (C). (A) Ventral medullary astrocytes visualized by Case12 fluorescence. Adenovirus containing the gene for Case12 (a genetically encoded Ca2+ indicator) under the control of a glial specific promotor was injected into the ventral medullary surface of rats and tissue examined 7 to 10 days later. Left, arrows point at glia limitans. Right, penetrating arteriole enwrapped by astrocyte processes expressing Case12. Coronal brainstem sections (50 μm) from two individual rats (). (B) Membrane potential of a phox2b positive retrotrapezoid nucleus (RTN) neuron illustrating its responses to light activation of adjacent ChR2(H134R)‐expressing astrocytes in the absence (left), presence (middle), or after washout (right) of MRS2179. Adapted, with permission, from reference (). (C) Time‐condensed record from an anesthetized rat illustrating effects of repeated stimulations of ventral medullary surface astrocytes on phrenic nerve activity before and after a single application of MRS2179 (100 μM, 20 μL) on the ventral surface. Spontaneous recovery of the response over time can be seen. The rat is apneic (not breathing) in the absence of photostimulation because it is experiencing hypocapnic apnea, which was induced by means of mechanical hyperventilation to reduce arterial levels of PCO2/[H+] below the apneic threshold. IPNA, integrated phrenic nerve activity; TP, tracheal pressure; ABP, arterial blood pressure, RR, respiratory rate. Adapted, with permission, from reference ().

Figure 12. Figure 12.

pH sensitivity of phox2b‐expressing chemosensitive retrotrapezoid nucleus (RTN) neurons in organotypic culture from 8‐ to 10‐day‐old rats is dependent on P2R signaling. (A) (Left) Image of the ventral aspect of an organotypic brainstem slice showing EGFP‐labeled Phox2b‐expressing RTN neurons, one of which is patch clamped. (Right) Time‐condensed record of the membrane potential of an RTN neuron responding to acidification in the absence and presence of the P2R antagonist, MRS2179. AP, action potentials (truncated); R, resistance tests using current pulses. (B) Summary of MRS2179 effect on pH‐evoked depolarizations in phox2b‐expressing RTN neurons. (C) (Left) Effect of MRS2179 on acidification‐induced intracellular Ca2+ response of an RTN neuron (ratiometric imaging using TN‐XXL, a genetically encoded Ca2+ indicator). (Right) RTN neurons expressing TN‐XXL under PRSx8 promotor control. (D) Summary data showing significant effect of MRS2179 on pH‐evoked intracellular Ca2+ responses of RTN neurons. Adapted, with permission, from reference ().

Figure 13. Figure 13.

Chemosensory retrotrapezoid nucleus (RTN) neurons (i.e., phox2b neurons) in acute slices from 7‐ to 12‐day‐old rats are sensitive to ATP but their pH sensitivity is not dependent on ATP signaling. (A) Firing rate plot illustrating the excitatory effect of local pressure application of UTP (uridine triphosphate 1 mM, P2YR agonist) in a representative pH‐sensitive RTN neuron; the UTP‐evoked increase in firing was unaffected by block of ionotropic glutamate receptors with CNQX and APV (10 and 50 μM). B, In a different pH‐sensitive RTN neuron, the UTP‐stimulated firing was blocked by the P2R antagonist reactive blue 2 (RB2, 50 μM), but pH sensitivity was retained. (C) P2 receptors do not mediate pH sensitivity in RTN chemoreceptors. Summary data illustrating averaged (±SEM) firing rate at normal pH (7.3) and during bath acidification (pH 6.9) and alkalization (pH 7.5), under control conditions and in the presence of the P2 receptor antagonists PPADS (100 μM, n = 4) or RB2 (20‐50 μM, n = 10). There was no difference in pH sensitivity before or during P2R blockade; that is, the slope of the relationship between firing rate and bath pH was similar in control and following block of P2Rs. (Note: the chemosensory RTN neurons in this study were not identified as phox2b neurons but their behavior is entirely consistent with previously identified phox2b labeled, chemosensory RTN neurons). Adapted, with permission, from reference ().

Figure 14. Figure 14.

Schematic of P2R signaling and its contribution to central chemosensitivity in the retrotrapezoid nucleus (RTN). Elevated CO2 in the blood diffuses across the blood vessel/capillary wall, increasing CO2 and H+ in the extracellular space surrounding neurons and astrocytes (). Astrocytes near the ventral medullary surface including those in the glia limitans respond in two ways. Depicted in the middle astrocyte, elevated CO2 (intracellular or extracellular) evokes release of ATP through CO2‐sensitive Cx26 hemichannels (i.e., Cx26 hemichannels act as the CO2 sensor) (). Depicted in the right astrocyte, CO2 or H+ also cause the release of intracellular Ca2+ () and Ca2+‐dependent, exocytotic release of ATP (). ATP released via one or both of these mechanisms excites chemosensitive RTN neurons through a P2Y (), G‐protein coupled receptor‐dependent mechanism that either modulates an unknown membrane conductance () or acid‐sensitive ion channels directly (). RTN neurons are also directly sensitive to intra‐ or extracellular acidification; the H+ sensor may be a K+ channel that is open at rest and closes in response to increased H+ (). Note, however, that while closure of a K+ channel is strongly implicated in the depolarization of RTN neurons by acid, there is no direct evidence that the depolarization is produced by the direct action of acid or CO2 on the K+ channel. Increased output from the RTN to the ventral respiratory column (VRC) including the pre‐BötC () causes ventilation to increase. The ATP‐dependent excitatory processes mediate approximately 25% of the central chemosensory response. The remainder of the response reflects direct activation of RTN and other chemosensory neurons. Additional actions of extracellular ATP appear to include a P2XR‐mediated, presynaptic excitation of inhibitory GABAergic inputs to RTN neurons () (the factors determining the balance to excitatory P2Y and indirect inhibitory P2XR mechanisms are not known) and an autocrine/paracrine P2YR‐mediated excitation of astrocytes (). ATP also has complex actions on the vasculature. Under conditions of normal oxygenation in other brain regions, ATP causes the contraction of vascular smooth muscle () as well pericytes (). The resultant reduction in blood flow is hypothesized to increase the CO2/pH stimulus and increase the response of local neurons/astrocytes. However, under conditions of reduced oxygen (hypoxia), there is growing evidence that the effects of ATP on both smooth muscle and pericytes reverses and facilitates restoration of blood flow to the hypoxic tissue. Whether the hypoxia‐dependent effects of ATP on the vasculature influence CO2/pH sensitivity of any respiratory chemosensory structure remains to be established.

Figure 15. Figure 15.

Effects of exogenously applied ATP on inspiratory motor output are biphasic. (A) Response of integrated C4 nerve root activity (∫C4) to application of ATP (10 mM, 60 s) over the C4 spinal cord (with pia removed) of a brainstem‐spinal cord preparation. (B) Time course of changes in ∫C4 inspiratory burst amplitude produced by 60 s local applications of 10 mM ATP (triangles) or 10 mM ATPγS (an hydrolysis‐resistant ATP analogue, closed circles) to the phrenic motoneuron column (n=5). Adapted with permission from (). (C) Response of integrated XII nerve root activity (∫XII) to application of ATP (1.0 mM, 30 s) into the XII nucleus of the medullary slice preparation. (D) Time course of the changes in ∫XII inspiratory burst amplitude evoked by local application of ATP (1 mM) before (open circles) and during, (triangles) local application of theophylline (100 μM; n = 8). Adapted, with permission, from reference (); values are means ± SE. * indicates significant difference from values at the same time during the control ATP application.



Figure 1.

When ATP is released into the extracellular space, it acts via a three‐part signaling system comprising: (i) the actions of ATP (and ADP) at P2Rs; (ii) diverse ecto‐nucleotidases with differential substrate affinities that degrade ATP and its byproducts ultimately to adenosine (ADO); and, (iii) the actions of ADO at P1Rs. (Ecto 5′, ecto‐5′‐ectonucleotidase; ENPPs, ectonucleotide pyrophosphatase/phosphodiesterease; TNAP, tissue nonspecific alkaline phosphatase).



Figure 2.

Purinergic signaling has multiple roles in shaping the biphasic ventilatory response to hypoxia. (A) The hypoxic ventilatory response, shown here from anesthetized piglets (green) and adult pigs (blue) exposed to 6% inspired O2, is biphasic. It comprises an initial increase followed by a gradual decline, referred to as the secondary depression or “roll‐off.” Note that despite a similar initial increase (upward arrows), compare to adults (blue downward arrow), the roll‐off is more pronounced in neonates (green downward arrow) where ventilation falls below baseline (green shading) [Adapted, with permission, from reference ()]. (B) In the carotid body, the P2X2 receptor subunit is a major contributor to the initial increase in ventilation that is evoked by hypoxia in mice. The graph shows respiratory responses (plotted as change in minute ventilation (E) from control) to varying levels of hypoxia in conscious wild‐type (blue) and P2X2‐deficient (green) mice. Adapted, with permission, from reference (). (C and D) ATP released within the ventral respiratory column during hypoxia offsets the magnitude of the secondary respiratory depression. Traces in (C) illustrate changes in the arterial blood pressure (ABP), integrated phrenic nerve discharge (∫Phrenic), and null and ATP sensor currents (measured at the ventral medullary surface immediately ventral to the ventral respiratory column) during exposure to systemic hypoxia (10% O2 in the inspired air). Prior to hypoxia, rats were mechanically hyperventilated to induce central apnea (arterial PCO2 and end‐tidal CO2 below apneic threshold). Note that the release of ATP at the ventral surface of the medulla oblongata occurs after the initial increase in phrenic nerve activity. (D) P2 receptor blockade in the ventrolateral medulla augments the hypoxia‐induced secondary depression of ventilation in adult rats. Summary data show the effect of pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS, P2 receptor antagonist) on changes in minute ventilation evoked by hypoxia. *Significant difference from control response, P < 0.05. Adapted, with permission, from reference (). (E) During hypoxia, adenosine (ADO) contributes to the secondary depression of ventilation. Curves illustrate ventilatory responses of decerebrate rabbit pups to 6% O2 during saline infusion (control) or following infusion of ADO antagonists (aminophylline, 25 mg kg−1; or 8‐p‐sulfophenyltheophylline, 5 mg kg−1). Ventilation is expressed as percent of the prehypoxic level (% control). Adapted, with permission, from reference ().



Figure 3.

Carotid body chemoreceptor function: location, purinergic signaling mechanisms and central projections. (A) The carotid bodies are located bilaterally in the neck at the bifurcation of the common carotid artery into the internal and external carotid arteries. (B) Enlarged view of the box in (A) showing the carotid body and its afferent innervation via the carotid sinus nerve. (C) Enlarged view of a cross‐section through the carotid body (at the blue line in B) showing arrangement of glomus cells (Type I cells; the sensors), sustentacular cells (Type II cells; glia‐like), capillaries and carotid sinus nerve and parasympathetic nerve endings (efferent axon). Signal transducation pathways for conversion of decreased O2 (lower Glomus cell [steps 1‐8]) increased CO2 (upper Glomus cell [steps i‐vii + 8]) and into transmitter release and action potential generation in carotid sinus nerve are depicted. Autocrine (step I) and paracrine (step II) actions of ATP and ADO (step 8) are also depicted. (D) Dorsal view of the medulla and pons showing central projections of carotid sinus nerve afferent fibers in the medulla. The first‐order excitatory synapse is in the nucleus tractus solitarius (NTS). These neurons project to the pontine respiratory group (PRG) and chemosensitive neurons in the parafacial respiratory group/retrofacial nucleus (pFRG/RTN) that in turn send excitatory projections to the pre‐BötC and possibly other regions of the ventral respiratory column. Note that while this diagram focuses on purinergic signaling in the carotid body, additional small molecule neurotransmitters and neuromodulators contribute to chemosensory processing in the rat carotid body.



Figure 4.

Proposed model of the three‐part ATP signaling system operating at the tripartite, glutamatergic inspiratory synapse (comprising pre‐ and postsynaptic neurons and astrocytes) in the ventral respiratory column and pre‐BötC. A volley of action potentials in presynaptic neuron during inspiration evokes glutamate (Glu) release (), which excites the postsynaptic neuron via ionotropic (GluR) and metabotropic (mGluR) glutamate receptors. When ATP is released into the extracellular space (), it directly activates P2Y1Rs on neurons () and glia (). In glia, ATP evokes an increase in Ca2+ () (via mechanisms outlined in Figure ), which leads to the exocytotic release of gliotransmitters ATP, glutamate (Glu) (), and D‐serine (not shown). Glu indirectly excites the postsynaptic neuron through ionotropic (AMPA and NMDAR) or mGluRs () while ATP acts via P2Rs that couple through phospholipase C and protein kinase C (PKC) and modulate membrane ion channels (see Figure ). ATP also acts in autocrine/paracrine manner to enhance gliotransmitter release (). ATP is degraded by ectonucleotidases (), producing ADP (which activates P2Y1Rs, not shown) and adenosine (ADO), which acts on presynaptic P1Rs to inhibit Glu release () and postsynaptic P1Rs (), causing hyperpolarization via activation of KATP channels.



Figure 5.

The pre‐BötC and pre‐BötC respiratory neurons are sensitive to ATP. (A) Rhythmic XII nerve activity recorded from a rat medullary slice preparation showing a dramatic increase in burst frequency following local injection of ATP (100 μM, 10 s) or the nonhydrolyzable ATP analogue, ATPγS (100 μM, 10 s) into the pre‐BötC. (B) Current‐clamp recording from a respiratory neuron displaying voltage‐dependent bursting behavior. In the top trace of membrane potential (VM), bursts occur at the same frequency as the XII nerve (∫XII). Spontaneous burst frequency increases when cell is depolarized from −65 to −60 and −55 mV. C. This neuron responded to local application of the P2YR agonist, 2MeSADP (1 mM), with an inward current (IM = membrane current) or depolarization. (D) Whole‐cell recording from a nonpacemaker respiratory neuron that responds to ATP and 2MeSADP with an inward current or depolarization. (A) Adapted, with permission, from reference () (B‐D) from reference ()).



Figure 6.

Glia contribute to the increase in inspiratory‐related frequency evoked by ATP in the pre‐BötC in vitro. Rhythmic inspiratory‐related activity recorded as integrated XII nerve activity (∫XII) from a rat medullary slice illustrates frequency increases evoked by local application of ATP (0.1 mM, 10 s, A) and SP (1 μM, 10 s, B) into the pre‐BötC during control conditions (left panels) and after disruption of rhythm by bath application (1‐2 h) of the glial toxin [methionine sulfoxamine (MSO, 0.1 mM)] and the subsequent restoration of rhythm by bath application of glutamine (GLN, 1.5 mM, middle panels] (n = 7). (*Significant difference between ATP responses, P < 0.001. Adapted, with permission, from reference ().



Figure 7.

Signaling cascades through which ATP is hypothesized to affect astrocytes and subsequently neuronal excitability. Extracellular ATP activates astrocytic P2Y, including P2Y1, receptors (), activating the Gαq/11 second messenger cascade () which acts through PLC, PIP2 and IP3 () to evoke the release of Ca2+ from intracellular stores (). Increased Ca2+ triggers exocytotic release of ATP, glutamate, and D‐serine (). Astrocytic ATP can act in an autocrine/paracrine manner on other astrocytes to evoke further transmitter release (ATP‐evoked ATP release) and propagate Ca2+ waves through local glial networks (). ATP is also hypothesized to excite local neurons, in part via P2Y1Rs () and the Gαq/11 second messenger pathway (), which, via activation of PKC (), modulates membrane ion channels including ICAN () to increase excitability. Astrocytic glutamate will act in an autocrine/ paracrine manner on astrocytes via mGluRs (not shown) and increase neuronal excitability through activation of glutamate receptors (mGluRs, AMPA, NMDA) (). Astrocytic D‐serine, a positive allosteric modulator of the NMDA subtype of glutamate receptor, may also increase excitability by potentiating NMDA currents (). Abbreviations: DAG, diacyl‐glycerol; ER, endoplasmic reticulum; Glu, glutamate; IP3, inositol trisphosposphate; mGluR, metabotropic glutamate receptor; PIP2, phosphatidylinositol 4,5‐bisphosphate; PKC, protein kinase C; PLC, phospholipase C; R, receptor).



Figure 8.

Local application of ATP into the pre‐BötC evokes a frequency response that closely follows the ATP concentration profile. (A) Schematic of the experimental setup showing the rhythmic medullary slice, triple‐barrel drug pipette for pressure injecting drugs (ATP) and the ATP and null sensors, all placed within the pre‐BötC. ATP (100 μ, 10 s) is injected into the pre‐BötC (site 1) and the ATP concentration within the pre‐BotC (difference current between null and ATP sensor currents) and inspiratory frequency are monitored (recorded from the XII nerve via a suction electrode). The drug injection pipette is then moved away from the pre‐BötC to site 2 (140 μm from site 1). (B) Trace of integrated XII nerve activity (∫XII) showing the rapid frequency response evoked by ATP in site 1. (C) Plots showing (for the same medullary slice preparation shown in B) the effects of locally applying ATP within the pre‐BötC (starting at t = 0) on inspiratory frequency (blue trace) and the ATP difference current (ATP sensor current‐null sensor current) within the pre‐BötC (green). (D) Inspiratory frequency and ATP difference current recorded in response to locally applying ATP at site 2. This more distant injection produces a different ATP concentration profile within the pre‐BötC, and, importantly, the frequency response still follows the ATP concentration profile measured within the pre‐BötC. Adapted, with permission, from reference ().



Figure 9.

Differential purinergic modulation of pre‐BötC rhythm in rhythmic medullary slice preparations from mouse and rat. (A) P2Y1R activation in the pre‐BötC increases frequency in mouse and rat. Integrated XII nerve (∫XII) recordings showing responses to local application of the P2Y1R agonist MRS 2365 (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (B) Differential effects of ATP on pre‐BötC rhythm in mouse and rat. ∫XII recordings showing responses to local application of and ATP (0.1 mM, 10 s) in the pre‐BötC of rat and mouse. (C) DPCPX (an A1 ADOR antagonist) in the pre‐BötC of mouse unmasks an ATP‐mediated frequency increase. ∫XII recordings showing responses to local application of ATP (0.1 mM, 10 s; left trace) under control conditions and after a 90 s preapplication of an A1R antagonist (2 μM DPCPX; right trace). (D) Real‐time polymerase chain reaction analysis reveals differential expression of ectonucleotidase isoforms in tissue punches from mouse and rat. The percentage contribution of each ectonucleotidase isoform to the total ectonucleotidase mRNA expressed in pre‐BötC punches from rat (n = 4) and mouse (n = 6). Error bars indicate SEM. co.# indicates copy number. *Significant difference between the compared columns. Adapted, with permission, from reference ().



Figure 10.

ATP released at the ventral medullary surface contributes to the hypercapnic ventilatory response via a P2R mechanism. (A) Rapid CO2‐induced release of ATP from the ventral surface of the medulla. An increase in the level of inspired CO2 in an adult anesthetized rat that had been hyperventilated to depress respiratory activity. Traces show changes in ATP and null sensor currents, respiratory activity (integrated phrenic nerve discharge, ∫phrenic) and respiratory frequency (fR) and end‐tidal CO2. The “Net ATP” trace represents the difference in signal between ATP and null sensors. (B) Expanded portion of A illustrating that ATP release precedes (arrow) respiratory activation. (C) Placement of sensors on the ventral surface of the medulla (py, pyramidal tract). The sensor surface is the entire platinum wire in contact with the ventral surface. Subsequent studies used small circular sensors to define ATP release sites along the ventral medullary surface (). (D) ATP receptor blockade on the chemosensitive areas of the ventral medullary surface attenuates the effect of CO2 on breathing in rats. Sequential recordings illustrating the effect of increasing concentrations of the P2 antagonist pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulfonate (PPADS) on the threshold level of end‐tidal CO2 level required to induce respiratory activity from hypocapnic apnoea. (E) Summary data (mean ± standard error) showing the increase in threshold levels of end‐tidal CO2 required to induce breathing from apnoea in the presence of PPADS (white columns; n = 8) or TNP‐ATP (black columns; n = 7) on the ventral medullary surface. * indicates significant difference, P < 0.05. Adapted, with permission, from reference ().



Figure 11.

Optogenetic stimulation of channel Rhodopsin 2‐expressing astrocytes on the ventral medullary surface activated phox2b positive chemoreceptor neurons via an ATP‐dependent mechanism and triggered robust respiratory responses in vivo (C). (A) Ventral medullary astrocytes visualized by Case12 fluorescence. Adenovirus containing the gene for Case12 (a genetically encoded Ca2+ indicator) under the control of a glial specific promotor was injected into the ventral medullary surface of rats and tissue examined 7 to 10 days later. Left, arrows point at glia limitans. Right, penetrating arteriole enwrapped by astrocyte processes expressing Case12. Coronal brainstem sections (50 μm) from two individual rats (). (B) Membrane potential of a phox2b positive retrotrapezoid nucleus (RTN) neuron illustrating its responses to light activation of adjacent ChR2(H134R)‐expressing astrocytes in the absence (left), presence (middle), or after washout (right) of MRS2179. Adapted, with permission, from reference (). (C) Time‐condensed record from an anesthetized rat illustrating effects of repeated stimulations of ventral medullary surface astrocytes on phrenic nerve activity before and after a single application of MRS2179 (100 μM, 20 μL) on the ventral surface. Spontaneous recovery of the response over time can be seen. The rat is apneic (not breathing) in the absence of photostimulation because it is experiencing hypocapnic apnea, which was induced by means of mechanical hyperventilation to reduce arterial levels of PCO2/[H+] below the apneic threshold. IPNA, integrated phrenic nerve activity; TP, tracheal pressure; ABP, arterial blood pressure, RR, respiratory rate. Adapted, with permission, from reference ().



Figure 12.

pH sensitivity of phox2b‐expressing chemosensitive retrotrapezoid nucleus (RTN) neurons in organotypic culture from 8‐ to 10‐day‐old rats is dependent on P2R signaling. (A) (Left) Image of the ventral aspect of an organotypic brainstem slice showing EGFP‐labeled Phox2b‐expressing RTN neurons, one of which is patch clamped. (Right) Time‐condensed record of the membrane potential of an RTN neuron responding to acidification in the absence and presence of the P2R antagonist, MRS2179. AP, action potentials (truncated); R, resistance tests using current pulses. (B) Summary of MRS2179 effect on pH‐evoked depolarizations in phox2b‐expressing RTN neurons. (C) (Left) Effect of MRS2179 on acidification‐induced intracellular Ca2+ response of an RTN neuron (ratiometric imaging using TN‐XXL, a genetically encoded Ca2+ indicator). (Right) RTN neurons expressing TN‐XXL under PRSx8 promotor control. (D) Summary data showing significant effect of MRS2179 on pH‐evoked intracellular Ca2+ responses of RTN neurons. Adapted, with permission, from reference ().



Figure 13.

Chemosensory retrotrapezoid nucleus (RTN) neurons (i.e., phox2b neurons) in acute slices from 7‐ to 12‐day‐old rats are sensitive to ATP but their pH sensitivity is not dependent on ATP signaling. (A) Firing rate plot illustrating the excitatory effect of local pressure application of UTP (uridine triphosphate 1 mM, P2YR agonist) in a representative pH‐sensitive RTN neuron; the UTP‐evoked increase in firing was unaffected by block of ionotropic glutamate receptors with CNQX and APV (10 and 50 μM). B, In a different pH‐sensitive RTN neuron, the UTP‐stimulated firing was blocked by the P2R antagonist reactive blue 2 (RB2, 50 μM), but pH sensitivity was retained. (C) P2 receptors do not mediate pH sensitivity in RTN chemoreceptors. Summary data illustrating averaged (±SEM) firing rate at normal pH (7.3) and during bath acidification (pH 6.9) and alkalization (pH 7.5), under control conditions and in the presence of the P2 receptor antagonists PPADS (100 μM, n = 4) or RB2 (20‐50 μM, n = 10). There was no difference in pH sensitivity before or during P2R blockade; that is, the slope of the relationship between firing rate and bath pH was similar in control and following block of P2Rs. (Note: the chemosensory RTN neurons in this study were not identified as phox2b neurons but their behavior is entirely consistent with previously identified phox2b labeled, chemosensory RTN neurons). Adapted, with permission, from reference ().



Figure 14.

Schematic of P2R signaling and its contribution to central chemosensitivity in the retrotrapezoid nucleus (RTN). Elevated CO2 in the blood diffuses across the blood vessel/capillary wall, increasing CO2 and H+ in the extracellular space surrounding neurons and astrocytes (). Astrocytes near the ventral medullary surface including those in the glia limitans respond in two ways. Depicted in the middle astrocyte, elevated CO2 (intracellular or extracellular) evokes release of ATP through CO2‐sensitive Cx26 hemichannels (i.e., Cx26 hemichannels act as the CO2 sensor) (). Depicted in the right astrocyte, CO2 or H+ also cause the release of intracellular Ca2+ () and Ca2+‐dependent, exocytotic release of ATP (). ATP released via one or both of these mechanisms excites chemosensitive RTN neurons through a P2Y (), G‐protein coupled receptor‐dependent mechanism that either modulates an unknown membrane conductance () or acid‐sensitive ion channels directly (). RTN neurons are also directly sensitive to intra‐ or extracellular acidification; the H+ sensor may be a K+ channel that is open at rest and closes in response to increased H+ (). Note, however, that while closure of a K+ channel is strongly implicated in the depolarization of RTN neurons by acid, there is no direct evidence that the depolarization is produced by the direct action of acid or CO2 on the K+ channel. Increased output from the RTN to the ventral respiratory column (VRC) including the pre‐BötC () causes ventilation to increase. The ATP‐dependent excitatory processes mediate approximately 25% of the central chemosensory response. The remainder of the response reflects direct activation of RTN and other chemosensory neurons. Additional actions of extracellular ATP appear to include a P2XR‐mediated, presynaptic excitation of inhibitory GABAergic inputs to RTN neurons () (the factors determining the balance to excitatory P2Y and indirect inhibitory P2XR mechanisms are not known) and an autocrine/paracrine P2YR‐mediated excitation of astrocytes (). ATP also has complex actions on the vasculature. Under conditions of normal oxygenation in other brain regions, ATP causes the contraction of vascular smooth muscle () as well pericytes (). The resultant reduction in blood flow is hypothesized to increase the CO2/pH stimulus and increase the response of local neurons/astrocytes. However, under conditions of reduced oxygen (hypoxia), there is growing evidence that the effects of ATP on both smooth muscle and pericytes reverses and facilitates restoration of blood flow to the hypoxic tissue. Whether the hypoxia‐dependent effects of ATP on the vasculature influence CO2/pH sensitivity of any respiratory chemosensory structure remains to be established.



Figure 15.

Effects of exogenously applied ATP on inspiratory motor output are biphasic. (A) Response of integrated C4 nerve root activity (∫C4) to application of ATP (10 mM, 60 s) over the C4 spinal cord (with pia removed) of a brainstem‐spinal cord preparation. (B) Time course of changes in ∫C4 inspiratory burst amplitude produced by 60 s local applications of 10 mM ATP (triangles) or 10 mM ATPγS (an hydrolysis‐resistant ATP analogue, closed circles) to the phrenic motoneuron column (n=5). Adapted with permission from (). (C) Response of integrated XII nerve root activity (∫XII) to application of ATP (1.0 mM, 30 s) into the XII nucleus of the medullary slice preparation. (D) Time course of the changes in ∫XII inspiratory burst amplitude evoked by local application of ATP (1 mM) before (open circles) and during, (triangles) local application of theophylline (100 μM; n = 8). Adapted, with permission, from reference (); values are means ± SE. * indicates significant difference from values at the same time during the control ATP application.

References
 1. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA, Weisman GA. International Union of Pharmacology LVIII: Update on the P2Y G protein‐coupled nucleotide receptors: From molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58: 281‐341, 2006.
 2. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H. Purinergic signalling in the nervous system: An overview. Trends Neurosci 32: 19‐29, 2009.
 3. Ainslie PN, Duffin J. Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: Mechanisms of regulation, measurement, and interpretation. Am J Physiol Regul Integr Comp Physiol 296: R1473‐R1495, 2009.
 4. Ainslie PN, Ogoh S. Regulation of cerebral blood flow in mammals during chronic hypoxia: A matter of balance. Exp Physiol 95: 251‐262, 2009.
 5. Arrenberg AB, Del Bene F, Baier H. Optical control of zebrafish behavior with halorhodopsin. Proc Natl Acad Sci U S A 106: 17968‐17973, 2009.
 6. Aston‐Jones G, Bloom FE. Activity of norepinephrine‐containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep‐waking cycle. J Neurosci 1: 876‐886, 1981.
 7. Balcar VJ, Dias LS, Li Y, Bennett MR. Inhibition of [3H]CGP 39653 binding to NMDA receptors by a P2 antagonist, suramin. Neuroreport 7: 69‐72, 1995.
 8. Ballanyi K. Neuromodulation of the perinatal respiratory network. Curr Neuropharmacol 2: 221‐243, 2004.
 9. Ballanyi K. Protective role of neuronal KATP channels in brain hypoxia. J Exp Biol 207: 3201‐3212, 2004.
 10. Baqi Y, Lee SY, Iqbal J, Ripphausen P, Lehr A, Scheiff AB, Zimmermann H, Bajorath J, Muller CE. Development of potent and selective inhibitors of ecto‐5′‐nucleotidase based on an anthraquinone scaffold. J Med Chem 53: 2076‐2086, 2010.
 11. Bellingham MC, Berger AJ. Adenosine suppresses excitatory glutamatergic inputs to rat hypoglossal motoneurons in vitro. Neurosci Lett 177: 143‐146, 1994.
 12. Bhatt‐Mehta V, Schumacher RE. Treatment of apnea of prematurity. Paediatr Drugs 5: 195‐210, 2003.
 13. Bisgard GE, Forster HV, Klein JP. Recovery of peripheral chemoreceptor function after denervation in ponies. J Appl Physiol 49: 964‐970, 1980.
 14. Bissonnette JM. Mechanisms regulating hypoxic respiratory depression during fetal and postnatal life. Am J Physiol Regul Integr Comp Physiol 278: R1391‐R1400, 2000.
 15. Bissonnette JM, Hohimer AR, Chao CR, Knopp SJ, Notoroberto NF. Theophylline stimulates fetal breathing movements during hypoxia. Pediatr Res 28: 83‐86, 1990.
 16. Bissonnette JM, Hohimer AR, Knopp SJ. The effect of centrally administered adenosine on fetal breathing movements. Respir Physiol 84: 273‐285, 1991.
 17. Bjelobaba I, Nedeljkovic N, Subasic S, Lavrnja I, Pekovic S, Stojkov D, Rakic L, Stojiljkovic M. Immunolocalization of ecto‐nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) in the rat forebrain. Brain Res 1120: 54‐63, 2006.
 18. Bjelobaba I, Stojiljkovic M, Pekovic S, Dacic S, Lavrnja I, Stojkov D, Rakic L, Nedeljkovic N. Immunohistological determination of ecto‐nucleoside triphosphate diphosphohydrolase1 (NTPDase1) and 5′‐nucleotidase in rat hippocampus reveals overlapping distribution. Cell Mol Neurobiol 27: 731‐743, 2007.
 19. Blain GM, Smith CA, Henderson KS, Dempsey JA. Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO(2). J Physiol 588: 2455‐2471, 2010.
 20. Bochorishvili G, Stornetta RL, Coates MB, Guyenet PG. Pre‐Botzinger complex receives glutamatergic innervation from galaninergic and other retrotrapezoid nucleus neurons. J Comp Neurol 520: 1047‐1061, 2012.
 21. Bofill‐Cardona E, Vartian N, Nanoff C, Freissmuth M, Boehm S. Two different signaling mechanisms involved in the excitation of rat sympathetic neurons by uridine nucleotides. Mol Pharmacol 57: 1165‐1172, 2000.
 22. Bonham AC, Coles SK, McCrimmon DR. Pulmonary stretch receptor afferents activate excitatory amino acid receptors in the nucleus tractus solitarii in rats. J Physiol 464: 725‐745 1993.
 23. Boue‐Grabot E, Barajas‐Lopez C, Chakfe Y, Blais D, Belanger D, Emerit MB, Seguela P. Intracellular cross talk and physical interaction between two classes of neurotransmitter‐gated channels. J Neurosci 23: 1246‐1253, 2003.
 24. Boue‐Grabot E, Emerit MB, Toulme E, Seguela P, Garret M. Cross‐talk and co‐trafficking between rho1/GABA receptors and ATP‐gated channels. J Biol Chem 279: 6967‐6975, 2004.
 25. Braccialli AL, Bonagamba LG, Machado BH. Glutamatergic and purinergic mechanisms on respiratory modulation in the caudal NTS of awake rats. Respir Physiol Neurobiol 161: 246‐252, 2008.
 26. Braga VA, Soriano RN, Braccialli AL, de Paula PM, Bonagamba LG, Paton JF, Machado BH. Involvement of L‐glutamate and ATP in the neurotransmission of the sympathoexcitatory component of the chemoreflex in the commissural nucleus tractus solitarii of awake rats and in the working heart‐brainstem preparation. J Physiol 581: 1129‐1145, 2007.
 27. Brake AJ, Wagenbach MJ, Julius D. New structural motif for ligand‐gated ion channels defined by an ionotropic ATP receptor. Nature 371: 519‐523, 1994.
 28. Braun N, Lenz C, Gillardon F, Zimmermann M, Zimmermann H. Focal cerebral ischemia enhances glial expression of ecto‐5′‐nucleotidase. Brain Res 766: 213‐226, 1997.
 29. Braun N, Sevigny J, Mishra SK, Robson SC, Barth SW, Gerstberger R, Hammer K, Zimmermann H. Expression of the ecto‐ATPase NTPDase2 in the germinal zones of the developing and adult rat brain. Eur J Neurosci 17: 1355‐1364, 2003.
 30. Braun N, Zhu Y, Krieglstein J, Culmsee C, Zimmermann H. Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the rat. J Neurosci 18: 4891‐4900, 1998.
 31. Breen S, Rees S, Walker D. Identification of brainstem neurons responding to hypoxia in fetal and newborn sheep. Brain Res 748: 107‐121, 1997.
 32. Brockhaus J, Ballanyi K. Anticonvulsant A(1) receptor‐mediated adenosine action on neuronal networks in the brainstem‐spinal cord of newborn rats. Neuroscience 96: 359‐371, 2000.
 33. Brosenitsch T, Lipski J, Housley GD, Funk GD. Developmental downregulation of ATP receptors in esophageal motoneurons (MNs). Abstract Viewer/Itinerary Planner: Washington, DC Society for Neuroscience Program No 409.11, 2003.
 34. Brosenitsch TA, Adachi T, Lipski J, Housley GD, Funk GD. Developmental downregulation of P2X3 receptors in motoneurons of the compact formation of the nucleus ambiguus. Eur J Neurosci 22: 809‐824, 2005.
 35. Brown DA, Filippov AK, Barnard EA. Inhibition of potassium and calcium currents in neurones by molecularly‐defined P2Y receptors. J Auton Nerv Syst 81: 31‐36, 2000.
 36. Brown P, Dale N. Modulation of K(+) currents in Xenopus spinal neurons by p2y receptors: A role for ATP and ADP in motor pattern generation. J Physiol 540: 843‐850, 2002.
 37. Brunschweiger A, Iqbal J, Umbach F, Scheiff AB, Munkonda MN, Sevigny J, Knowles AF, Muller CE. Selective nucleoside triphosphate diphosphohydrolase‐2 (NTPDase2) inhibitors: Nucleotide mimetics derived from uridine‐5′‐carboxamide. J Med Chem 51: 4518‐4528, 2008.
 38. Burnstock G. The past, present and future of purine nucleotides as signalling molecules. Neuropharmacology 36: 1127‐1139, 1997.
 39. Burnstock G. Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87: 659‐797, 2007.
 40. Burnstock G. Purinergic regulation of vascular tone and remodelling. Auton Autacoid Pharmacol 29: 63‐72, 2009.
 41. Burnstock G, Fredholm BB, Verkhratsky A. Adenosine and ATP receptors in the brain. Curr Top Med Chem 11: 973‐1011, 2011.
 42. Burr D, Sinclair JD. The effect of adenosine on respiratory chemosensitivity in the awake rat. Respir Physiol 72: 47‐57, 1988.
 43. Butt AM. ATP: A ubiquitous gliotransmitter integrating neuron‐glial networks. Semin Cell Dev Biol 22: 205‐213, 2011.
 44. Buttigieg J, Nurse CA. Detection of hypoxia‐evoked ATP release from chemoreceptor cells of the rat carotid body. Biochem Biophys Res Commun 322: 82‐87, 2004.
 45. Campanucci VA, Nurse CA. Autonomic innervation of the carotid body: Role in efferent inhibition. Respir Physiol Neurobiol 157: 83‐92, 2007.
 46. Campanucci VA, Zhang M, Vollmer C, Nurse CA. Expression of multiple P2X receptors by glossopharyngeal neurons projecting to rat carotid body O2‐chemoreceptors: Role in nitric oxide‐mediated efferent inhibition. J Neurosci 26: 9482‐9493, 2006.
 47. Card JP, Sved JC, Craig B, Raizada M, Vazquez J, Sved AF. Efferent projections of rat rostroventrolateral medulla C1 catecholamine neurons: Implications for the central control of cardiovascular regulation. J Comp Neurol 499: 840‐859, 2006.
 48. Cardenas H, Zapata P. Ventilatory reflexes originated from carotid and extracarotid chemoreceptors in rats. Am J Physiol 244: R119‐R125, 1983.
 49. Cass CE, Young JD, Baldwin SA. Recent advances in the molecular biology of nucleoside transporters of mammalian cells. Biochem Cell Biol 76: 761‐770, 1998.
 50. Chan E, Steenland HW, Liu H, Horner RL. Endogenous excitatory drive modulating respiratory muscle activity across sleep‐wake states. Am J Respir Crit Care Med 174: 1264‐1273, 2006.
 51. Chow YW, Wang HL. Functional modulation of P2X2 receptors by cyclic AMP‐dependent protein kinase. J Neurochem 70: 2606‐2612, 1998.
 52. Close LN, Cetas JS, Heinricher MM, Selden NR. Purinergic receptor immunoreactivity in the rostral ventromedial medulla. Neuroscience 158: 915‐921, 2009.
 53. Cognato Gde P, Bruno AN, da Silva RS, Bogo MR, Sarkis JJ, Bonan CD. Antiepileptic drugs prevent changes induced by pilocarpine model of epilepsy in brain ecto‐nucleotidases. Neurochem Res 32: 1046‐1055, 2007.
 54. Collo G, North RA, Kawashima E, Merlo‐Pich E, Neidhart S, Surprenant A, Buell G. Cloning OF P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP‐gated ion channels. J Neurosci 16: 2495‐2507, 1996.
 55. Comer AM, Perry CM, Figgitt DP. Caffeine citrate: A review of its use in apnoea of prematurity. Paediatr Drugs 3: 61‐79, 2001.
 56. Conde SV, Monteiro EC. Hypoxia induces adenosine release from the rat carotid body. J Neurochem 89: 1148‐1156, 2004.
 57. Corcoran AE, Hodges MR, Wu Y, Wang W, Wylie CJ, Deneris ES, Richerson GB. Medullary serotonin neurons and central CO2 chemoreception. Respir Physiol Neurobiol 168: 49‐58, 2009.
 58. Corriden R, Insel PA, Junger WG. A novel method using fluorescence microscopy for real‐time assessment of ATP release from individual cells. Am J Physiol Cell Physiol 293: C1420‐C1425, 2007.
 59. Crowder EA, Saha MS, Pace RW, Zhang H, Prestwich GD, Del Negro CA. Phosphatidylinositol 4,5‐bisphosphate regulates inspiratory burst activity in the neonatal mouse preBotzinger complex. J Physiol 582: 1047‐1058, 2007.
 60. Dale N, Gilday D. Regulation of rhythmic movements by purinergic neurotransmitters in frog embryos. Nature 383: 259‐263, 1996.
 61. Darnall RA. Aminophylline reduces hypoxic ventilatory depression: Possible role of adenosine. Pediatr Res 19: 19: 706‐710, 1985.
 62. Davenport HW, Brewer G, and et al. The respiratory responses to anoxemia of unanesthetized dogs with chronically denervated aortic and carotid chemoreceptors and their causes. Am J Physiol 148: 406‐416, 1947.
 63. Dawes GS, Gardner WN, Johnston BM, Walker DW. Breathing in fetal lambs: The effect of brain stem section. J Physiol 335: 535‐553, 1983.
 64. de Paula Cognato G, Bruno AN, Vuaden FC, Sarkis JJ, Bonan CD. Ontogenetic profile of ectonucleotidase activities from brain synaptosomes of pilocarpine‐treated rats. Int J Dev Neurosci 23: 703‐709, 2005.
 65. Dean JB, Putnam RW. The caudal solitary complex is a site of central CO(2) chemoreception and integration of multiple systems that regulate expired CO(2). Respir Physiol Neurobiol 173: 274‐287, 2010.
 66. Depuy SD, Kanbar R, Coates MB, Stornetta RL, Guyenet PG. Control of breathing by raphe obscurus serotonergic neurons in mice. J Neurosci 31: 1981‐1990, 2011.
 67. Dong XW, Feldman JL. Modulation of inspiratory drive to phrenic motoneurons by presynaptic adenosine A1 receptors. J Neurosci 15: 3458‐3467, 1995.
 68. Dulla CG, Dobelis P, Pearson T, Frenguelli BG, Staley KJ, Masino SA. Adenosine and ATP link PCO2 to cortical excitability via pH. Neuron 48: 1011‐1023, 2005.
 69. Easton P, Anthonisen NR. Ventilatory response to sustained hypoxia after pretreatment with aminophylline. J Appl Physiol 64: 1445‐1450, 1988.
 70. Edwards FA, Gibb AJ, Colquhoun D. ATP receptor‐mediated synaptic currents in the central nervous system [see comments]. Nature 359: 144‐147, 1992.
 71. Eldridge FL, Millhorn DE, Kiley JP. Respiratory effects of a long‐acting analog of adenosine. Brain Res 310: 273‐280, 1984.
 72. Eldridge FL, Millhorn DE, Kiley JP. Antagonism by theophylline of respiratory inhibition induced by adenosine. J Appl Physiol 59: 1428‐1433, 1985.
 73. Evans RJ, Derkach V, Surprenant A. ATP mediates fast synaptic transmission in mammalian neurons. Nature 357: 503‐505, 1992.
 74. Favier R, Lacaisse A. [O2 chemoreflex drive of ventilation in the awake rat (author's transl)]. J Physiol (Paris) 74: 411‐417, 1978.
 75. Feldman JL, Mitchell GS, Nattie EE. Breathing: Rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26: 239‐266, 2003.
 76. Fellin T, Pascual O, Haydon PG. Astrocytes coordinate synaptic networks: Balanced excitation and inhibition. Physiology (Bethesda) 21: 208‐215, 2006.
 77. Fenik VB, Davies RO, Kubin L. Noradrenergic, serotonergic and GABAergic antagonists injected together into the XII nucleus abolish the REM sleep‐like depression of hypoglossal motoneuronal activity. J Sleep Res 14: 419‐429, 2005.
 78. Figueiredo M, Lane S, Tang F, Liu BH, Hewinson J, Marina N, Kasymov V, Souslova EA, Chudakov DM, Gourine AV, Teschemacher AG, Kasparov S. Optogenetic experimentation on astrocytes. Exp Physiol 96: 40‐50, 2010.
 79. Filippov AK, Fernandez‐Fernandez JM, Marsh SJ, Simon J, Barnard EA, Brown DA. Activation and inhibition of neuronal G protein‐gated inwardly rectifying K(+) channels by P2Y nucleotide receptors. Mol Pharmacol 66: 468‐477, 2004.
 80. Filippov AK, Webb TE, Barnard EA, Brown DA. P2Y2 nucleotide receptors expressed heterologously in sympathetic neurons inhibit both N‐type Ca2+ and M‐type K+ currents. J Neurosci 18: 5170‐5179, 1998.
 81. Finer NN, Higgins R, Kattwinkel J, Martin RJ. Summary proceedings from the apnea‐of‐prematurity group. Pediatrics 117: S47‐S51, 2006.
 82. Fong A, Krstew E, Barden J, Lawrence A. Immunoreactive localisation of P2Y(1) receptors within the rat and human nodose ganglia and rat brainstem: Comparison with [alpha(33)P]deoxyadenosine 5′‐triphosphate autoradiography. Neuroscience 113: 809, 2002.
 83. Forster HV, Bisgard GE, Klein JP. Effect of peripheral chemoreceptor denervation on acclimatization of goats during hypoxia. J Appl Physiol 50: 392‐398, 1981.
 84. Frenguelli BG, Wigmore G, Llaudet E, Dale N. Temporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampus. J Neurochem 101: 1400‐1413, 2007.
 85. Fuller RW, Maxwell DL, Conradson TB, Dixon CM, Barnes PJ. Circulatory and respiratory effects of infused adenosine in conscious man. Br J Clin Pharmacol 24: 309‐317, 1987.
 86. Funk GD, Huxtable AG, Lorier AR. ATP in central respiratory control: A three‐part signaling system. Respir Physiol Neurobiol 164: 131‐142, 2008.
 87. Funk GD, Kanjhan R, Walsh C, Lipski J, Comer AM, Parkis MA, Housley GD. P2 receptor excitation of rodent hypoglossal motoneuron activity in vitro and in vivo: A molecular physiological analysis. J Neurosci 17: 6325‐6337, 1997.
 88. Funk GD, Parkis MA, Selvaratnam SR, Walsh C. Developmental modulation of glutamatergic inspiratory drive to hypoglossal motoneurons. Respir Physiol 110: 125‐137, 1997.
 89. Funk GD, Smith JC, Feldman JL. Development of thyrotropin‐releasing hormone and norepinephrine potentiation of inspiratory‐related hypoglossal motoneuron discharge in neonatal and juvenile mice in vitro. J Neurophysiol 72: 2538‐2541, 1994.
 90. Gargaglioni LH, Hartzler LK, Putnam RW. The locus coeruleus and central chemosensitivity. Respir Physiol Neurobiol 173: 264‐273, 2010.
 91. Gershan WM, Forster HV, Lowry TF, Garber A, K. Effect of theophylline on ventilatory roll‐off during hypoxia in goats. Respir Physiol 103: 157‐164, 1996.
 92. Gluckman PD, Johnston BM. Lesions in the upper lateral pons abolish the hypoxic depression of breathing in unanaesthetized fetal lambs in utero. J Physiol 382: 373‐383, 1987.
 93. Gordon GR, Baimoukhametova DV, Hewitt SA, Rajapaksha WR, Fisher TE, Bains JS. Norepinephrine triggers release of glial ATP to increase postsynaptic efficacy. Nat Neurosci 8: 1078‐1086, 2005.
 94. Gordon GR, Choi HB, Rungta RL, Ellis‐Davies GC, MacVicar BA. Brain metabolism dictates the polarity of astrocyte control over arterioles. Nature 456: 745‐749, 2008.
 95. Gordon GR, Mulligan SJ, MacVicar BA. Astrocyte control of the cerebrovasculature. GLIA 55: 1214‐1221, 2007.
 96. Gourine AV. On the peripheral and central chemoreception and control of breathing: An emerging role of ATP. J Physiol 568.3: 715‐724, 2005.
 97. Gourine AV, Atkinson L, Deuchars J, Spyer KM. Purinergic signalling in the medullary mechanisms of respiratory control in the rat: Respiratory neurones express the P2X2 receptor subunit. J Physiol 552: 197‐211, 2003.
 98. Gourine AV, Dale N, Korsak A, Llaudet E, Tian F, Huckstepp R, Spyer KM. Release of ATP and glutamate in the nucleus tractus solitarii mediate pulmonary stretch receptor (Breuer‐Hering) reflex pathway. J Physiol 586: 3963‐3978, 2008.
 99. Gourine AV, Kasparov S. Astrocytes as brain interoceptors. Exp Physiol 96: 411‐416, 2011.
 100. Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, Lane S, Teschemacher AG, Spyer KM, Deisseroth K, Kasparov S. Astrocytes control breathing through pH‐dependent release of ATP. Science 329: 571‐575, 2010.
 101. Gourine AV, Llaudet E, Dale N, Spyer KM. ATP is a mediator of chemosensory transduction in the central nervous system. Nature 436: 108‐111, 2005.
 102. Gourine AV, Llaudet E, Dale N, Spyer KM. Release of ATP in the ventral medulla during hypoxia in rats: Role in hypoxic ventilatory response. J Neurosci 25: 1211‐1218, 2005.
 103. Gourine AV, Llaudet E, Thomas T, Dale N, Spyer KM. Adenosine release in nucleus tractus solitarii does not appear to mediate hypoxia‐induced respiratory depression in rats. J Physiol 544: 161‐170, 2002.
 104. Gourine AV, Spyer KM. Chemosensitivity of medullary respiratory neurones. A role for ionotropic P2X and GABA(A) receptors. Adv Exp Med Biol 536: 375‐387, 2003.
 105. Grass D, Pawlowski PG, Hirrlinger J, Papadopoulos N, Richter DW, Kirchhoff F, Hülsmann S. Diversity of functional astroglial properties in the respiratory network. J Neurosci 24: 1358‐1365, 2004.
 106. Greer JJ, Funk GD, Ballanyi K. Preparing for the first breath: Prenatal maturation of respiratory neural control. J Physiol 570: 437‐444, 2006.
 107. Griffiths TL, Christie JM, Parsons ST, Holgate ST. The effect of dipyridamole and theophylline on hypercapnic ventilatory responses: The role of adenosine. Eur Respir J 10: 156‐160, 1997.
 108. Griffiths TL, Warren SJ, Chant AD, Holgate ST. Ventilatory effects of hypoxia and adenosine infusion in patients after bilateral carotid endarterectomy. Clin Sci (Lond) 78: 25‐31, 1990.
 109. Guyenet PG, Stornetta RL, Bayliss DA. Central respiratory chemoreception. J Comp Neurol 518: 3883‐3906, 2010.
 110. Halassa MM, Fellin T, Haydon PG. Tripartite synapses: Roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology 57: 343‐346, 2009.
 111. Halassa MM, Haydon PG. Integrated brain circuits: Astrocytic networks modulate neuronal activity and behavior. Annu Rev Physiol 72: 335‐355, 2010.
 112. Hamilton NB, Attwell D. Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci 11: 227‐238, 2010.
 113. Hamilton NB, Attwell D, Hall CN. Pericyte‐mediated regulation of capillary diameter: A component of neurovascular coupling in health and disease. Front Neuroenergetics 2: 2010.
 114. Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86: 1009‐1031, 2006.
 115. Hedner T, Hedner J, Bergman B, Mueller RA, Jonason J. Characterization of adenosine‐induced respiratory depression in the preterm rabbit. Biol Neonate 47: 323‐332, 1985.
 116. Hedner T, Hedner J, Jonason J, Wessberg P. Effects of theophylline on adenosine‐induced respiratory depression in the preterm rabbit. Eur J Respir Dis 65: 153‐156, 1984.
 117. Heine P, Braun N, Heilbronn A, Zimmermann H. Functional characterization of rat ecto‐ATPase and ecto‐ATP diphosphohydrolase after heterologous expression in CHO cells. Eur J Biochem 262: 102‐107, 1999.
 118. Herlenius E, Aden U, Tang LQ, Lagercrantz H. Perinatal respiratory control and its modulation by adenosine and caffeine in the rat. Pediatr Res 51: 4‐12, 2002.
 119. Herlenius E, Lagercrantz H. Adenosinergic modulation of respiratory neurones in the neonatal rat brainstem in vitro. J Physiol 518 (Pt 1): 159‐172, 1999.
 120. Herlenius E, Lagercrantz H, Yamamoto Y. Adenosine modulates inspiratory neurons and the respiratory pattern in the brainstem of neonatal rats. Pediatr Res 42: 46‐53, 1997.
 121. Horner RL. Emerging principles and neural substrates underlying tonic sleep‐state‐dependent influences on respiratory motor activity. Philos Trans R Soc Lond B Biol Sci 364: 2553‐2564, 2009.
 122. Huckstepp RT, Eason R, Sachdev A, Dale N. CO2‐dependent opening of connexin 26 and related {beta} connexins. J Physiol 588: 3921‐3931, 2010.
 123. Huckstepp RT, Id Bihi R, Eason R, Spyer KM, Dicke N, Willecke K, Marina N, Gourine AV, Dale N. Connexin hemichannel‐mediated CO2‐dependent release of ATP in the medulla oblongata contributes to central respiratory chemosensitivity. J Physiol 588: 3901‐3920, 2010.
 124. Huxtable AG, Zwicker JD, Alvares TS, Ruangkittisakul A, Fang X, Hahn LB, Posse de Chaves E, Baker GB, Ballanyi K, Funk GD. Glia contribute to the purinergic modulation of inspiratory rhythm‐generating networks. J Neurosci 30: 3947‐3958, 2010.
 125. Huxtable AG, Zwicker JD, Poon BY, Pagliardini S, Vrouwe SQ, Greer JJ, Funk GD. Tripartite purinergic modulation of central respiratory networks during perinatal development: The influence of ATP, ectonucleotidases, and ATP metabolites. J Neurosci 29: 14713‐14725, 2009.
 126. Illes P, Verkhratsky A, Burnstock G, Franke H. P2X receptors and their roles in astroglia in the central and peripheral nervous system. Neuroscientist (Epub, PMID: 22013151) 2011.
 127. Iqbal J, Vollmayer P, Braun N, Zimmermann H, Muller CE. A capillary electrophoresis method for the characterization of ecto‐nucleoside triphosphate diphosphohydrolases (NTPDases) and the analysis of inhibitors by in‐capillary enzymatic microreaction. Purinergic Signal 1: 349‐358, 2005.
 128. Ireland MF, Noakes PG, Bellingham MC. P2X7‐like receptor subunits enhance excitatory synaptic transmission at central synapses by presynaptic mechanisms. Neuroscience 128: 269‐280, 2004.
 129. Jakovcevic D, Harder DR. Role of astrocytes in matching blood flow to neuronal activity. Curr Top Dev Biol 79: 75‐97, 2007.
 130. Kaneda K, Kasahara H, Matsui R, Katoh T, Mizukami H, Ozawa K, Watanabe D, Isa T. Selective optical control of synaptic transmission in the subcortical visual pathway by activation of viral vector‐expressed halorhodopsin. PLoS One 6: e18452, 2011.
 131. Kanjhan R, Housley GD, Burton LD, Christie DL, Kippenberger A, Thorne PR, Luo L, Ryan AF. Distribution of the P2X2 receptor subunit of the ATP‐gated ion channels in the rat central nervous system. J Comp Neurol 407: 11‐32, 1999.
 132. Kato F, Shigetomi E, Yamazaki K, Tsuji N, Takano K. A dual‐role played by extracellular ATP in frequency‐filtering of the nucleus Tractus solitarii network. Adv Exp Med Biol 551: 151‐156, 2004.
 133. Kawai A, Ballantyne D, Muckenhoff K, Scheid P. Chemosensitive medullary neurones in the brainstem–spinal cord preparation of the neonatal rat. J Physiol 492: 277‐292, 1996.
 134. Kawai A, Okada Y, Muckenhoff K, Scheid P. Theophylline and hypoxic ventilatory response in the rat isolated brainstem‐spinal cord. Respir Physiol 100: 25‐32, 1995.
 135. Kawamura M, Gachet C, Inoue K, Kato F. Direct excitation of inhibitory interneurons by extracellular ATP mediated by P2Y1 receptors in the hippocampal slice. J Neurosci 24: 10835‐10845, 2004.
 136. Kegel B, Braun N, Heine P, Maliszewski CR, Zimmerman H. An ecto‐ATPase and an ecto‐ATP diphospohydrolase are expressed rat brain. Neuropharmacology 36: 1189‐1200, 1997.
 137. Khakh BS, Fisher JA, Nashmi R, Bowser DN, Lester HA. An angstrom scale interaction between plasma membrane ATP‐gated P2X2 and alpha4beta2 nicotinic channels measured with fluorescence resonance energy transfer and total internal reflection fluorescence microscopy. J Neurosci 25: 6911‐6920, 2005.
 138. King BF, Wildman SS, Ziganshina LE, Pintor J, Burnstock G. Effects of extracellular pH on agonism and antagonism at a recombinant P2X2 receptor. Br J Pharmacol 121: 1445‐1453, 1997.
 139. Kobayashi K, Lemke RP, Greer JJ. Development of fetal breathing movements in the rat. J Appl Physiol 91: 316‐320, 2001.
 140. Koles L, Leichsenring A, Rubini P, Illes P. P2 receptor signaling in neurons and glial cells of the central nervous system. Adv Pharmacol 61: 441‐493, 2011.
 141. Koos BJ. Adenosine Aa receptors and O sensing in development. Am J Physiol Regul Integr Comp Physiol 301: R601‐R622, 2011.
 142. Koos BJ, Chau A. Fetal cardiovascular and breathing responses to an adenosine A2a receptor agonist in sheep. Am J Physiol 274: R152‐R159, 1998.
 143. Koos BJ, Chau A, Matsuura M, Punla O, Kruger L. Thalamic locus mediates hypoxic inhibition of breathing in fetal sheep. J Neurophysiol 79: 2383‐2393, 1998.
 144. Koos BJ, Kawasaki Y, Kim YH, Bohorquez F. Adenosine A2A‐receptor blockade abolishes the roll‐off respiratory response to hypoxia in awake lambs. Am J Physiol Regul Integr Comp Physiol 288: R1185‐R1194, 2005.
 145. Koos BJ, Kruger L, Murray TF. Source of extracellular brain adenosine during hypoxia in fetal sheep. Brain Res 778: 439‐442, 1997.
 146. Koos BJ, Maeda T, Jan C. Adenosine A(1) and A(2A) receptors modulate sleep state and breathing in fetal sheep. J Appl Physiol 91: 343‐350, 2001.
 147. Koos BJ, Maeda T, Jan C, Lopez G. Adenosine A(2A) receptors mediate hypoxic inhibition of fetal breathing in sheep. Am J Obstet Gynecol 186: 663‐668, 2002.
 148. Koos BJ, Mason BA, Punla O, Adinolfi AM. Hypoxic inhibition of breathing in fetal sheep: Relationship to brain adenosine concentrations. J Appl Physiol 77: 2734‐2739, 1994.
 149. Koos BJ, Matsuda K. Fetal breathing, sleep state and cardiovascular responses to adenosine in sheep. J Appl Physiol 68: 489‐495, 1990.
 150. Kukulski F, Levesque SA, Lavoie EG, Lecka J, Bigonnesse F, Knowles AF, Robson SC, Kirley TL, Sevigny J. Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8. Purinergic Signal 1: 193‐204, 2005.
 151. Kukulski F, Sevigny J, Komoszynski M. Comparative hydrolysis of extracellular adenine nucleotides and adenosine in synaptic membranes from porcine brain cortex, hippocampus, cerebellum and medulla oblongata. Brain Res 1030: 49‐56, 2004.
 152. Kumar P, Prabhakar N. Sensing hypoxia: Carotid body mechanisms and reflexes in health and disease. Respir Physiol Neurobiol 157: 1‐3, 2007.
 153. Kumar P, Prabhakar NR. Peripheral chemoreceptors: Function and plasticity of the carotid body. Comp Physiol 141‐219, 2012.
 154. Lagercrantz H, Yamamoto Y, Fredholm BB, Prabhakar NR, Euler C. Adenosine analogues depress ventilation in rabbit neonates. Theophylline stimulation of respiration via adenosine receptors. Paediatr Res 18: 387‐390, 1984.
 155. Lahiri S, Roy A, Baby SM, Hoshi T, Semenza GL, Prabhakar NR. Oxygen sensing in the body. Prog Biophys Mol Biol 91: 249‐286, 2006.
 156. Langer D, Hammer K, Koszalka P, Schrader J, Robson S, Zimmermann H. Distribution of ectonucleotidases in the rodent brain revisited. Cell Tissue Res 334: 199‐217, 2008.
 157. Larsson M, Sawada K, Morland C, Hiasa M, Ormel L, Moriyama Y, Gundersen V. Functional and anatomical identification of a vesicular transporter mediating neuronal ATP release. Cereb Cortex 22: 1203‐1214.
 158. Lazarenko RM, Milner TA, Depuy SD, Stornetta RL, West GH, Kievits JA, Bayliss DA, Guyenet PG. Acid sensitivity and ultrastructure of the retrotrapezoid nucleus in Phox2b‐EGFP transgenic mice. J Comp Neurol 517: 69‐86, 2009.
 159. Lee SY, Wolff SC, Nicholas RA, O'Grady SM. P2Y receptors modulate ion channel function through interactions involving the C‐terminal domain. Mol Pharmacol 63: 878‐885, 2003.
 160. Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, Hirrlinger PG, Kirchhoff F, Bissonnette JM, Ballas N, Mandel G. A role for glia in the progression of Rett's syndrome. Nature 475: 497‐500.
 161. Llaudet E, Hatz S, Droniou M, Dale N. Microelectrode biosensor for real‐time measurement of ATP in biological tissue. Anal Chem 77: 3267‐3273, 2005.
 162. Long WQ, Anthonisen NR. Aminophylline partially blocks ventilatory depression with hypoxia in the awake cat. Can J Physiol Pharmacol 72: 673‐678, 1994.
 163. Lopes LV, Sebastiao AM, Ribeiro JA. Adenosine and related drugs in brain diseases: Present and future in clinical trials. Curr Top Med Chem 11: 1087‐1101, 2011.
 164. Lopez‐Barneo J, Ortega‐Saenz P, Pardal R, Pascual A, Piruat JI. Carotid body oxygen sensing. Eur Respir J 32: 1386‐1398, 2008.
 165. Lopez‐Barneo J, Ortega‐Saenz P, Pardal R, Pascual A, Piruat JI, Duran R, Gomez‐Diaz R. Oxygen sensing in the carotid body. Ann N Y Acad Sci 1177: 119‐131, 2009.
 166. Lorier AR, Huxtable AG, Robinson DM, Lipski J, Housley GD, Funk GD. P2Y1 receptor modulation of the pre‐Botzinger complex inspiratory rhythm generating network in vitro. J Neurosci 27: 993‐1005, 2007.
 167. Lorier AR, Lipski J, Housley GD, Greer JJ, Funk GD. ATP sensitivity of preBotzinger complex neurones in neonatal rat in vitro: Mechanism underlying a P2 receptor‐mediated increase in inspiratory frequency. J Physiol 586: 1429‐1446, 2008.
 168. Lorier AR, Peebles K, Brosenitsch T, Robinson DM, Housley GD, Funk GD. P2 receptors modulate respiratory rhythm but do not contribute to central CO2 sensitivity in vitro. Respir Physiol Neurobiol 142: 27‐42., 2004.
 169. Lutz PL. Mechanisms for anoxic survival in the vertebrate brain. Annu Rev Physiol 54: 601‐618, 1992.
 170. Lutz PL, Prentice HM. Sensing and responding to hypoxia, molecular and physiological mechanisms. Integr Comp Biol 42: 463‐468, 2002.
 171. Martin ED, Fernandez M, Perea G, Pascual O, Haydon PG, Araque A, Cena V. Adenosine released by astrocytes contributes to hypoxia‐induced modulation of synaptic transmission. GLIA 55: 36‐45, 2007.
 172. Martin‐Body RL, Johnston BM. Central origin of the hypoxic depression of breathing in the newborn. Respir Physiol 71: 25‐32, 1988.
 173. Martin‐Body RL, Robson GJ, Sinclair JD. Respiratory effects of sectioning the carotid sinus glossopharyngeal and abdominal vagal nerves in the awake rat. J Physiol 361: 35‐45, 1985.
 174. Maruo K, Yamamoto H, Yamamoto S, Nagata T, Fujikawa H, Kanno T, Yaguchi T, Maruo S, Yoshiya S, Nishizaki T. Modulation of P2X receptors via adrenergic pathways in rat dorsal root ganglion neurons after sciatic nerve injury. Pain 120: 106‐112, 2006.
 175. Mateo J, Harden TK, Boyer JL. Functional expression of a cDNA encoding a human ecto‐ATPase. Br J Pharmacol 128: 396‐402, 1999.
 176. Matsuka Y, Neubert JK, Maidment NT, Spigelman I. Concurrent release of ATP and substance P within guinea pig trigeminal ganglia in vivo. Brain Res 915: 248‐255, 2001.
 177. Mayer CA, Haxhiu MA, Martin RJ, Wilson CG. Adenosine A2A receptors mediate GABAergic inhibition of respiration in immature rats. J Appl Physiol 100: 91‐97, 2006.
 178. Mendoza‐Fernandez V, Andrew RD, Barajas‐Lopez C. ATP inhibits glutamate synaptic release by acting at P2Y receptors in pyramidal neurons of hippocampal slices. J Pharmacol Exp Ther 293: 172‐179, 2000.
 179. Miles GB, Parkis MA, Lipski J, Funk GD. Modulation of phrenic motoneuron excitability by ATP: Consequences for respiratory‐related output in vitro. J Appl Physiol 92: 1899‐1910, 2002.
 180. Miller MJ, Tenney SM. Hypoxia‐induced tachypnea in carotid‐deafferented cats. Respir Physiol 23: 31‐39, 1975.
 181. Mines AH, Sorensen SC. Ventilatory responses of awake normal goats during acute and chronic hypoxia. J Appl Physiol 28: 826‐831, 1970.
 182. Mironov SL, Langohr K, Richter DW. A1 adenosine receptors modulate respiratory activity of the neonatal mouse via the cAMP‐mediated signaling pathway. J Neurophysiol 81: 247‐255, 1999.
 183. Montandon G, Horner RL, Kinkead R, Bairam A. Caffeine in the neonatal period induces long‐lasting changes in sleep and breathing in adult rats. J Physiol 587: 5493‐5507, 2009.
 184. Montandon G, Kinkead R, Bairam A. Adenosinergic modulation of respiratory activity: Developmental plasticity induced by perinatal caffeine administration. Respir Physiol Neurobiol 164: 87‐95, 2008.
 185. Moore PJ, Ackland GL, Hanson MA. Unilateral cooling in the region of locus coeruleus blocks the fall in respiratory output during hypoxia in anaesthetized neonatal sheep. Exp Physiol 81: 983‐994, 1996.
 186. Mortola JP. Hypoxic hypometabolism in mammals. NIPS 8: 79‐82, 1993.
 187. Mortola JP. Ventilatory responses to hypoxia in mammals. In: Haddad GG, Lister G, editors. Tissue Oxygen Deprivation. New York: Marcel Dekker, 1996, pp. 433‐477.
 188. Mortola JP, Rezzonico R, Lanthier C. Ventilation and oxygen consumption in newborn mammals; a comparative analysis. Respir Physiol 78: 31‐43, 1989.
 189. Moss IR. Respiratory responses to single and episodic hypoxia during development: Mechanisms of adaptation. Respir Physiol 121: 185‐197, 2000.
 190. Motin L, Bennett MR. Effect of P2‐purinoceptor antagonists on glutamatergic transmission in the rat hippocampus. Br J Pharmacol 115: 1276‐1280, 1995.
 191. Mulkey DK, Mistry AM, Guyenet PG, Bayliss DA. Purinergic P2 receptors modulate excitability but do not mediate pH sensitivity of RTN respiratory chemoreceptors. J Neurosci 26: 7230‐7233, 2006.
 192. Mulkey DK, Rosin DL, West G, Takakura AC, Moreira TS, Bayliss DA, Guyenet PG. Serotonergic neurons activate chemosensitive retrotrapezoid nucleus neurons by a pH‐independent mechanism. J Neurosci 27: 14128‐14138, 2007.
 193. Mulkey DK, Stornetta RL, Weston MC, Simmons JR, Parker A, Bayliss DA, Guyenet PG. Respiratory control by ventral surface chemoreceptor neurons in rats. Nat Neurosci 7: 1360‐1369, 2004.
 194. Mulkey DK, Wenker IC, Kreneisz O. Current ideas on central chemoreception by neurons and glial cells in the retrotrapezoid nucleus. J Appl Physiol 108: 1433‐1439, 2010.
 195. Munkonda MN, Kauffenstein G, Kukulski F, Levesque SA, Legendre C, Pelletier J, Lavoie EG, Lecka J, Sevigny J. Inhibition of human and mouse plasma membrane bound NTPDases by P2 receptor antagonists. Biochem Pharmacol 74: 1524‐1534, 2007.
 196. Munkonda MN, Pelletier J, Ivanenkov VV, Fausther M, Tremblay A, Kunzli B, Kirley TL, Sevigny J. Characterization of a monoclonal antibody as the first specific inhibitor of human NTP diphosphohydrolase‐3: Partial characterization of the inhibitory epitope and potential applications. FEBS J 276: 479‐496, 2009.
 197. Nakazawa K, Inoue K, Ito K, Koizumi S, Inoue K. Inhibition by suramin and reactive blue 2 of GABA and glutamate receptor channels in rat hippocampal neurons. Naunyn Schmiedebergs Arch Pharmacol 351: 202‐208, 1995.
 198. Nattie E, Li A. Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol 106: 1464‐1466, 2009.
 199. Nishiyama A, Komitova M, Suzuki R, Zhu X. Polydendrocytes (NG2 cells): Multifunctional cells with lineage plasticity. Nat Rev Neurosci 10: 9‐22, 2009.
 200. Nurse CA. Neurotransmitter and neuromodulatory mechanisms at peripheral arterial chemoreceptors. Exp Physiol 95: 657‐667, 2010.
 201. Ogoh S, Ainslie PN. Cerebral blood flow during exercise: Mechanisms of regulation. J Appl Physiol 107: 1370‐1380, 2009.
 202. Olson EB, Jr, Vidruk EH, Dempsey JA. Carotid body excision significantly changes ventilatory control in awake rats. J Appl Physiol 64: 666‐671, 1988.
 203. Ong WY, Motin LG, Hansen MA, Dias LS, Ayrout C, Bennett MR, Balcar VJ. P2 purinoceptor blocker suramin antagonises NMDA receptors and protects against excitatory behaviour caused by NMDA receptor agonist (RS)‐(tetrazol‐5‐yl)‐glycine in rats. J Neurosci Res 49: 627‐638, 1997.
 204. Onimaru H, Ikeda K, Kawakami K. Postsynaptic mechanisms of CO2 responses in parafacial respiratory neurons of newborn rats. J Physiol 590: 1615‐1624, 2012.
 205. Parkinson FE, Damaraju VL, Graham K, Yao SY, Baldwin SA, Cass CE, Young JD. Molecular biology of nucleoside transporters and their distributions and functions in the brain. Curr Top Med Chem 11: 948‐972, 2011.
 206. Parkis MA, Bayliss DA, Berger AJ. Actions of norepinephrine on rat hypoglossal motoneurons. J Neurophysiol 74: 1911‐1919, 1995.
 207. Pearson T, Currie AJ, Etherington LA, Gadalla AE, Damian K, Llaudet E, Dale N, Frenguelli BG. Plasticity of purine release during cerebral ischemia: Clinical implications? J Cell Mol Med 7: 362‐375, 2003.
 208. Pena F, Ramirez JM. Hypoxia‐induced changes in neuronal network properties. Mol Neurobiol 32: 251‐283, 2005.
 209. Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature 443: 700‐704, 2006.
 210. Poelchen W, Sieler D, Wirkner K, Illes P. Co‐transmitter function of ATP in central catecholaminergic neurons of the rat. Neuroscience 102: 593‐602, 2001.
 211. Prabhakar NR. O2 sensing at the mammalian carotid body: Why multiple O2 sensors and multiple transmitters? Exp Physiol 91: 17‐23, 2006.
 212. Ralevic V, Thomas T, Spyer KM. Effects of P2 purine receptor agonists microinjected into the rostral ventrolateral medulla on the cardiovascular and respiratory systems of the anaesthetized rat. J Physiol 509.P: 127P, 1998.
 213. Ramirez JM, Quellmalz UJ, Wilken B. Developmental changes in the hypoxic response of the hypoglossus respiratory motor output in vitro. J Neurophysiol 78: 383‐392, 1997.
 214. Ramirez JM, Quellmalz UJ, Wilken B, Richter DW. The hypoxic response of neurones within the in vitro mammalian respiratory network. J Physiol 507: 571‐582, 1998.
 215. Reid PG, Watt AH, Penny WJ, Newby AC, Smith AP, Routledge PA. Plasma adenosine concentrations during adenosine‐induced respiratory stimulation in man. Eur J Clin Pharmacol 40: 175‐180, 1991.
 216. Remmers JE, Degroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 44: 931‐938, 1978.
 217. Reppert SM, Weaver DR, Stehle JH, Rivkees SA. Molecular cloning and characterization of a rat A1‐adenosine receptor that is widely expressed in brain and spinal cord. Mol Endocrinol 5: 1037‐1048, 1991.
 218. Ribeiro JA, Sebastiao AM. Caffeine and adenosine. J Alzheimers Dis 20 (Suppl 1): S3‐S15, 2010.
 219. Ribeiro JA, Sebastiao AM, de Mendonca A. Adenosine receptors in the nervous system: Pathophysiological implications. Prog Neurobiol 68: 377‐392, 2002.
 220. Richter DW, Schmidt‐Garcon P, Pierrefiche O, Bischoff AM, Lalley PM. Neurotransmitters and neuromodulators controlling the hypoxic respiratory response in anaesthetized cats [see comments]. J Physiol 514: 567‐578, 1999.
 221. Robson SC, Sevigny J, Zimmermann H. The E‐NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance. Purinergic Signal 2: 409‐430, 2006.
 222. Rong W, Gourine AV, Cockayne DA, Xiang Z, Ford AP, Spyer KM, Burnstock G. Pivotal role of nucleotide P2X2 receptor subunit of the ATP‐gated ion channel mediating ventilatory responses to hypoxia. J Neurosci 23: 11315‐11321, 2003.
 223. Rosin DL, Chang DA, Guyenet PG. Afferent and efferent connections of the rat retrotrapezoid nucleus. J Comp Neurol 499: 64‐89, 2006.
 224. Rosin DL, Robeva A, Woodard RL, Guyenet PG, Linden J. Immunohistochemical localization of adenosine A2A receptors in the rat central nervous system. J Comp Neurol 401: 163‐186, 1998.
 225. Ruangkittisakul A, Ballanyi K. Methylxanthine reversal of opioid‐evoked inspiratory depression via phosphodiesterase‐4 blockade. Respir Physiol Neurobiol 172: 94‐105, 2010.
 226. Runold M, Lagercrantz H, Fredholm BB. Ventilatory effect of an adenosine analogue in unanesthetized rabbits during development. J Appl Physiol 61: 255‐259, 1986.
 227. Runold M, Lagercrantz H, Prabhakar NR, Fredholm BB. Role of adenosine in hypoxic ventilatory depression. J Appl Physiol 67: 541‐546, 1989.
 228. Sauerland EK, Harper RM. The human tongue during sleep: Electromyographic activity of the genioglossus muscle. Exp Neurol 51: 160‐170, 1976.
 229. Sawada K, Echigo N, Juge N, Miyaji T, Otsuka M, Omote H, Yamamoto A, Moriyama Y. Identification of a vesicular nucleotide transporter. Proc Natl Acad Sci U S A 105: 5683‐5686, 2008.
 230. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W. Caffeine therapy for apnea of prematurity. N Engl J Med 354: 2112‐2121, 2006.
 231. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W. Long‐term effects of caffeine therapy for apnea of prematurity. N Engl J Med 357: 1893‐1902, 2007.
 232. Schmidt C, Bellingham MC, Richter DW. Adenosinergic modulation of respiratory neurones and hypoxic responses in the anaesthetized cat. J Physiol 483: 769‐781, 1995.
 233. Sebastiao AM, Ribeiro JA. Adenosine receptors and the central nervous system. Handb Exp Pharmacol (193): 471‐534, 2009.
 234. Selvaratnam SR, Parkis MA, Funk GD. Developmental modulation of mouse hypoglossal nerve inspiratory output in vitro by noradrenergic receptor agonists. Brain Res 805: 104‐115, 1998.
 235. Sim JA, Young MT, Suyng H‐Y, North AR, Surprenant A. Reanalysis of P2X7 receptor expression in rodent brain. J Neurosci 24 (28): 6307‐6314, 2004.
 236. Smith CA, Forster HV, Blain GM, Dempsey JA. An interdependent model of central/peripheral chemoreception: Evidence and implications for ventilatory control. Respir Physiol Neurobiol 173: 288‐297, 2010.
 237. Smith TM, Kirley TL. Cloning, sequencing, and expression of a human brain ecto‐apyrase related to both the ecto‐ATPases and CD39 ecto‐apyrases1. Biochim Biophys Acta 1386: 65‐78, 1998.
 238. Song X, Guo W, Yu Q, Liu X, Xiang Z, He C, Burnstock G. Regional expression of P2Y(4) receptors in the rat central nervous system. Purinergic Signal 7: 469‐488, 2011.
 239. Sorensen SC, Mines AH. Ventilatory responses to acute and chronic hypoxia in goats after sinus nerve section. J Appl Physiol 28: 832‐835, 1970.
 240. Spyer KM, Thomas T. A role for adenosine in modulating cardio‐respiratory responses: A mini‐review. Brain Res Bull 53: 121‐124, 2000.
 241. Stoop R, Surprenant A, North RA. Different sensitivities to pH of ATP‐induced currents at four cloned P2X receptors. J Neurophysiol 78: 1837‐1840, 1997.
 242. Stornetta RL, Rosin DL, Simmons JR, McQuiston TJ, Vujovic N, Weston MC, Guyenet PG. Coexpression of vesicular glutamate transporter‐3 and gamma‐aminobutyric acidergic markers in rat rostral medullary raphe and intermediolateral cell column. J Comp Neurol 492: 477‐494, 2005.
 243. Stornetta RL, Spirovski D, Moreira TS, Takakura AC, West GH, Gwilt JM, Pilowsky PM, Guyenet PG. Galanin is a selective marker of the retrotrapezoid nucleus in rats. J Comp Neurol 512: 373‐383, 2009.
 244. Sun MK, Wahlestedt C, Reis DJ. Action of externally applied ATP on rat reticulospinal vasomotor neurons. Eur J Pharmacol 224: 93‐96, 1992.
 245. Takakura AC, Moreira TS, Colombari E, West GH, Stornetta RL, Guyenet PG. Peripheral chemoreceptor inputs to retrotrapezoid nucleus (RTN) CO2‐sensitive neurons in rats. J Physiol 572: 503‐523, 2006.
 246. Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M. Astrocyte‐mediated control of cerebral blood flow. Nat Neurosci 9: 260‐267, 2006.
 247. Thoby‐Brisson M, Ramirez JM. Role of inspiratory pacemaker neurons in mediating the hypoxic response of the respiratory network in vitro. J Neurosci 20: 5858‐5866, 2000.
 248. Thomas T, Marshall JM. Interdependence of respiratory and cardiovascular changes induced by hypoxia in the rat: The roles of adenosine. J Physiol 480: 627‐636, 1994.
 249. Thomas T, Ralevic V, Bardini M, Burnstock G, Spyer KM. Evidence for the involvement of purinergic signalling in the control of respiration. Neuroscience 107: 481‐490, 2001.
 250. Thomas T, Ralevic V, Gadd CA, Spyer KM. Central CO2 chemoreception: A mechanism involving P2 purinoceptors localized in the ventrolateral medulla of the anaesthetized rat. J Physiol 517: 899‐905, 1999.
 251. Thomas T, Spyer KM. ATP as a mediator of mammalian central CO2 chemoreception. J Physiol 523 (Pt 2): 441‐447, 2000.
 252. Thomas T, St Lambert JH, Dashwood MR, Spyer KM. Localization and action of adenosine A2a receptors in regions of the brainstem important in cardiovascular control. Neuroscience 95: 513‐518, 2000.
 253. Torres IL, Buffon A, Silveira PP, Duarte MZ, Bassani MG, Oliveira SS, Battastini AM, Sarkis JJ, Dalmaz C, Ferreira MB. Effect of chronic and acute stress on ectonucleotidase activities in spinal cord. Physiol Behav 75: 1‐5, 2002.
 254. Trapp S, Aller MI, Wisden W, Gourine AV. A role for TASK‐1 (KCNK3) channels in the chemosensory control of breathing. J Neurosci 28: 8844‐8850, 2008.
 255. Trapp S, Tucker SJ, Gourine AV. Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16). Exp Physiol 96: 451‐459, 2011.
 256. Tsuda M, Tozaki‐Saitoh H, Inoue K. Pain and purinergic signaling. Brain Res Rev 63: 222‐232, 2009.
 257. Valera S, Hussy N, Evans RJ, Adami N, North RA, Surprenant A, Buell G. A new class of ligand‐gated ion channel defined by P2x receptor for extracellular ATP. Nature 371: 516‐519, 1994.
 258. Vandam RJ, Shields EJ, Kelty JD. Rhythm generation by the pre‐Botzinger complex in medullary slice and island preparations: Effects of adenosine A(1) receptor activation. BMC Neurosci 9: 95, 2008.
 259. Vandier C, Conway AF, Landauer RC, Kumar P. Presynaptic action of adenosine on a 4‐aminopyridine‐sensitive current in the rat carotid body. J Physiol 515 (Pt 2): 419‐429, 1999.
 260. Verkhratsky A, Krishtal OA, Burnstock G. Purinoceptors on neuroglia. Mol Neurobiol 39: 190‐208, 2009.
 261. von Kugelgen I. Pharmacological profiles of cloned mammalian P2Y‐receptor subtypes. Pharmacol Ther 110: 415‐432, 2006.
 262. Waites BA, Ackland GL, Noble R, Hanson MA. Red nucleus lesions abolish the biphasic respiratory response to isocapnic hypoxia in decerebrate young rabbits. J Physiol 495 (Pt 1): 217‐225, 1996.
 263. Wang JL, Wu ZH, Pan BX, Li J. Adenosine A1 receptors modulate the discharge activities of inspiratory and biphasic expiratory neurons in the medial region of Nucleus Retrofacialis of neonatal rat in vitro. Neurosci Lett 379: 27‐31, 2005.
 264. Wang TF, Guidotti G. CD39 is an ecto‐(Ca, Mg)‐apyrase. J Biol Chem 271: 9898‐9901, 1996.
 265. Waters KA, Gozal D. Responses to hypoxia during early development. Respir Physiol Neurobiol 136: 115‐129, 2003.
 266. Webb TE, Simon J, Krishek BJ, Bateson AN, Smart TG, King BF, Burnstock G, Barnard EA. Cloning and functional expression of a brain G‐protein‐coupled ATP receptor. FEBS Lett 324: 219‐225, 1993.
 267. Wenker IC, Kreneisz O, Nishiyama A, Mulkey DK. Astrocytes in the retrotrapezoid nucleus sense H +by inhibition of a Kir4.1‐Kir5.1‐like current and may contribute to chemoreception by a purinergic mechanism. J Neurophysiol 104: 3042‐3052, 2010.
 268. Wenker IC, Sobrinho CR, Takakura AC, Moreira TS, Mulkey DK. Regulation of ventral surface CO2/H+‐sensitive neurons by purinergic signalling. J Physiol 590: 2137‐2150, 2012.
 269. Wessberg P, Hedner J, Hedner T, Persson B, Jonason J. Adenosine mechanisms in the regulation of breathing in the rat. Eur J Pharmacol 106: 59‐67, 1984.
 270. Wilson CG, Martin RJ, Jaber M, Abu‐Shaweesh J, Jafri A, Haxhiu MA, Zaidi S. Adenosine A2A receptors interact with GABAergic pathways to modulate respiration in neonatal piglets. Respir Physiol Neurobiol 141: 201‐211, 2004.
 271. Xu F, Xu J, Tse FW, Tse A. Adenosine stimulates depolarization and rise in cytoplasmic [Ca2+] in type I cells of rat carotid bodies. Am J Physiol Cell Physiol 290: C1592‐C1598, 2006.
 272. Yamamoto M, Nishimura M, Kobayashi S, Akiyama Y, Miyamoto K, Kawakami Y. Role of endogenous adenosine in hypoxic ventilatory response in humans: A study with dipyridamole. J Appl Physiol 76: 196‐203, 1994.
 273. Yan S, Laferriere A, Zhang C, Moss IR. Microdialyzed adenosine in nucleus tractus solitarii and ventilatory response to hypoxia in piglets. J Appl Physiol 79: 405‐410, 1995.
 274. Yao ST, Barden JA, Finkelstein DI, Bennett MR, Lawrence AJ. Comparative study on the distribution patterns of P2X(1)‐P2X(6) receptor immunoreactivity in the brainstem of the rat and the common marmoset (Callithrix jacchus): Association with catecholamine cell groups. J Comp Neurol 427: 485‐507, 2000.
 275. Yao ST, Gourine AV, Spyer KM, Barden JA, Lawrence AJ. Localisation of P2X2 receptor subunit immunoreactivity on nitric oxide synthase expressing neurones in the brain stem and hypothalamus of the rat: A fluorescence immunohistochemical study. Neuroscience 121: 411‐419, 2003.
 276. Zaidi SI, Jafri A, Martin RJ, Haxhiu MA. Adenosine A2A receptors are expressed by GABAergic neurons of medulla oblongata in developing rat. Brain Res 1071: 42‐53, 2006.
 277. Zhang M, Zhong H, Vollmer C, Nurse CA. Co‐release of ATP and ACh mediates hypoxic signalling at rat carotid body chemoreceptors. J Physiol 525 (Pt 1): 143‐158, 2000.
 278. Zhao S, Cunha C, Zhang F, Liu Q, Gloss B, Deisseroth K, Augustine GJ, Feng G. Improved expression of halorhodopsin for light‐induced silencing of neuronal activity. Brain Cell Biol 36: 141‐154, 2008.
 279. Ziganshin AU, Hoyle CHV, Burnstock G. Ecto‐enzymes and metabolism of extracellular ATP. Drug Dev Res 32: 1994.
 280. Zimmermann H. Extracellular metabolism of ATP and other nucleotides. Naunyn Schmiedebergs Arch Pharmacol 362: 299‐309, 2000.
 281. Zimmermann H. Ectonucleotidases: Some recent developments and a note on nomenclature. Drug Development Research 52: 44‐56, 2001.
 282. Zimmermann H. Ectonucleotidases in the nervous system. Novartis Found Symp 276: 113‐128; discussion 128‐130, 233‐117, 275‐181, 2006.
 283. Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G. Neuron‐to‐astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci 6: 43‐50, 2003.
 284. Zwicker JD, Rajani V, Hahn LB, Funk GD. Purinergic modulation of preBotzinger complex inspiratory rhythm in rodents: The interaction between ATP and adenosine. J Physiol 589: 4583‐4600, 2011.

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Gregory D. Funk. Neuromodulation: Purinergic Signaling in Respiratory Control. Compr Physiol 2013, 3: 331-363. doi: 10.1002/cphy.c120004