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Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease

Emilio Carbone, Ricardo Borges, Lee E. Eiden, Antonio G. García, Arturo Hernández‐Cruz

10.1002/cphy.c190003

Source: Volume 9, Issue 4, October 2019

Published online: September 2019

Full Article on Wiley Online Library



Abstract

Chromaffin cells (CCs) of the adrenal gland and the sympathetic nervous system produce the catecholamines (epinephrine and norepinephrine; EPI and NE) needed to coordinate the bodily “fight‐or‐flight” response to fear, stress, exercise, or conflict. EPI and NE release from CCs is regulated both neurogenically by splanchnic nerve fibers and nonneurogenically by hormones (histamine, corticosteroids, angiotensin, and others) and paracrine messengers [EPI, NE, adenosine triphosphate, opioids, γ‐aminobutyric acid (GABA), etc.]. The “stimulus‐secretion” coupling of CCs is a Ca2+‐dependent process regulated by Ca2+ entry through voltage‐gated Ca2+ channels, Ca2+ pumps, and exchangers and intracellular organelles (RE and mitochondria) and diffusible buffers that provide both Ca2+‐homeostasis and Ca2+‐signaling that ultimately trigger exocytosis. CCs also express Na+ and K+ channels and ionotropic (nAChR and GABAA) and metabotropic receptors (mACh, PACAP, β‐AR, 5‐HT, histamine, angiotensin, and others) that make CCs excitable and responsive to autocrine and paracrine stimuli. To maintain high rates of E/NE secretion during stressful conditions, CCs possess a large number of secretory chromaffin granules (CGs) and members of the soluble NSF‐attachment receptor complex protein family that allow docking, fusion, and exocytosis of CGs at the cell membrane, and their recycling. This article attempts to provide an updated account of well‐established features of the molecular processes regulating CC function, and a survey of the as‐yet‐unsolved but important questions relating to CC function and dysfunction that have been the subject of intense research over the past 15 years. Examples of CCs as a model system to understand the molecular mechanisms associated with neurodegenerative diseases are also provided. Published 2019. Compr Physiol 9:1443‐1502, 2019.

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Figure 1. Figure 1. Different firing modes of spontaneously active chromaffin cells. (A, B) Spontaneous AP trains recorded from two different rat CCs displaying “irregular” and “regular” tonic firings, respectively. (C) Spontaneous AP trains exhibiting slow‐wave bursting recorded from a mouse CC. Below is shown a single burst at an expanded time scale (dashed rectangle) and the overlap of consecutive APs within a burst. Numbers indicate the sequential position in the burst. Adapted, with permission, from Vandael DH, et al., 2015 633.
Figure 2. Figure 2. Time course of Na+, Ca2+, and K+ currents during slow‐wave bursts in mouse CCs. (A) AP‐clamp experiment measuring Kv and BK currents. Top: AP bursts elicited by current steps were recorded at current‐clamp mode and used as voltage command (black trace) in voltage‐clamp experiments. Bottom: Kv currents are shown in red and BK currents in gray. (B, C) As in (A), but the currents isolated were Ca2+ currents (blue), SK (orange), and Na+ (black). (D) Top: BK, SK, and Kv outward current amplitudes versus the spike number of the burst. Bottom: Same, but for the Na+ and Ca2+ inward currents. Adapted, with permission, from Vandael DH, et al., 2015 633.
Figure 3. Figure 3. Low pHo induces burst firing in mouse CCs. Spontaneous firing (no current injection) recorded in mouse CCs at pHo 7.4, 7.0, and 6.6. Bottom: AP recordings on an expanded time scale corresponding to the gray window above. A decrease in pHo results in resting membrane depolarization and the switch of firing modes from tonic (pHo 7.4) to mildly bursting (pHo 7.0), to sustained bursting (pHo 6.6). Intermittent and sustained burst firing are accompanied by a net decrease of AP peak amplitude associated with the slow inactivation of Nav1.3 channels at depolarized potentials. The dotted line indicates the 0‐mV level. Adapted, with permission, from Guarina L, et al., 2017 260.
Figure 4. Figure 4. Spike frequency adaptation during current injections in mouse CCs. (A) Representative current‐clamp recordings from WT mouse CCs in response to 5, 10, or 15 pA current injection from Vh = −70 mV (from top to bottom). (B) Evolution of the instantaneous firing frequency in WT mouse CCs at 15 pA in control (black squares) and in the presence of the SK channel blocker apamin (200 nM; red circles). (C) AP recordings in the presence of 200 nM apamin during 15 pA current injection, to be compared with the control trace to the left. Adapted, with permission, from Vandael DHF, et al., 2012 635.
Figure 5. Figure 5. Voltage‐dependent modulation of CaV2.1 and CaV2.2 in CCs. (A) Acute application of ATP (50 μM) slows down the activation of N‐ and P/Q‐type Ba2+ currents recorded at 0 mV in a bovine CC (for details, see Ref. 98). (B) The delayed activation of N‐ and P/Q‐type Ba2+ currents induced by the acute application of met‐enkephalin (10 μM; black trace; control) is recovered by a 50‐ms prepulse step depolarization to +70 mV (red dot; red trace) (for details, see Ref. 573). (C) Acute application of the soluble vesicle lysate (SVL) containing (EPI, NE, opioids, and ATP) causes N‐ and P/Q‐type current delayed activation in bovine CCs (for details, see Ref. 10). (D, E) Autocrine inhibition of N‐ and P/Q‐type channels revealed by changing cell superfusion from “stop‐flow” to “flow” condition, in bovine CCs. In the “flow” condition, there is no autocrine inhibition. Ba2+ currents at 0 mV are fast activating. In the “stop‐flow” condition, the autocrine‐released material inhibits through GPCRs the opening of CaV2 (N‐ and P/Q‐type) channels, inducing marked activation delay. Adapted, with permission, from Carabelli V, et al., 1998 98. (F) Ba2+ currents recorded from a cell that is part of a cluster undergo robust autocrine modulation (black trace, control). A prepulse to +100 mV is able to rescue the fast channel activation by removing the autocrine inhibition induced by the neurotransmitters released by the surrounding cells (for details, see Ref. 290).
Figure 6. Figure 6. Up‐ and downmodulation of CaV1.2 and CaV1.3 channels by the cAMP/PKA and NO/cGMP/PKG pathways in mouse CCs. The top half illustrates the molecular components and the sequential steps of the β‐AR‐mediated upregulation of CaV1.2 and CaV1.3 L‐type channels through the activation of adenylate cyclase (AC), leading to cAMP production, activation of PKA, and CaV1 channel phosphorylation, causing an increase in open channel probability. The bottom part shows the molecular components and the sequential steps of the NO‐mediated downregulation of CaV1.2 and CaV1.3 L‐type channels through the activation of a soluble guanylate cyclase (sGC), leading to cGMP production, activation of PKG, and CaV1 channels phosphorylation, causing a decrease in open channel probability. NO is produced by membrane NO‐synthases. cGMP is also produced by a membrane guanylate cyclase (mGC). Adapted, with permission, from Mahapatra S, et al., 2012 417.
Figure 7. Figure 7. Synergistic effects of cAMP/PKA and cGMP/PKG pathways on Cav1 currents of WT mouse CCs. The right side is a schematic representation of CaV1 channel α1 subunit with two hypothetical PKA and PKG phosphorylation sites (P). The schemes represent the situation under basal conditions (middle), a synergistic potentiation (top), and a synergistic inhibition (bottom) of CaV1 channel. PKA and PKG P‐sites are partially phosphorylated (P) or unphosphorylated under resting conditions. Phosphorylation and dephosphorylation drove by up‐ and downregulation of PKA and PKG proceed independently of each other and can reach two extreme conditions. In one case, the two PKA P‐sites are dephosphorylated and the two PKG P‐sites are phosphorylated (minimal CaV1 current; cyan trace, on the top left panel). Alternatively, the PKA sites are phosphorylated and PKG P‐sites are dephosphorylated (maximal CaV1 current; cyan trace, on the bottom left panel). The two panels to the left show the time course of synergistic downregulation of CaV1 channels induced by the sequential application of the PKA inhibitor H‐89 and the PKG activator 8‐pCPT‐cGMP (top) and the synergistic upregulation of CaV1 channels by sequential application of the PKA activator forskolin and PKG inhibitor KT 5823 (bottom). Adapted, with permission, from Mahapatra S, et al., 2012 417; Adapted, with permission, from Vandael DHF, et al., 2013 634 (drawing and experimental data).
Figure 8. Figure 8. The concept of functional triads that regulate the generation of local [Ca2+]c transients and exocytosis responses upon stimulation of CCs. (1) After cell depolarization with the physiological neurotransmitter ACh, the voltage‐dependent Ca2+ channels open. (2) Ca2+ enters the cell through a huge electrochemical gradient, giving rise to the formation of a high‐Ca2+ microdomain (HCMD) of about 10 μM or higher near the sub‐plasmalemmal exocytotic sites. (3) High Ca2+ is required to trigger the fast exocytotic release of CAs. (4) The HCMD quickly dissipates initially by mobile Ca2+ buffers (not drawn) and more slowly by Ca2+ uptake by the ER Ca2+‐ATPase (SERCA). (5) The second more relevant pathway for the clearance of the [Ca2+]c transient is the mitochondrial Ca2+ uniporter, which has a low‐affinity high‐capacity for Ca2+ sequestration into the mitochondrial matrix. (6, 7) In both ER and mitochondria (Mito), the matrix [Ca2+]c can reach near half a millimolar. ER Ca2+ can be released back into the cytosol through a CICR mechanism via ryanodine receptors, lnsP3 receptors (6), or through the mitochondrial Na+/Ca2+ exchanger (7). (8) Ca2+ diffusion serves to redistribute Ca2+ at inner areas of the cell core to generate low‐Ca2+ microdomains (LCMD) of around half micromolar that are required for the cytoskeleton‐mediated Ca2+‐dependent vesicle traffic. (9) The Ca2+ levels of the LCMD refills with new vesicles the RRP at sub‐plasmalemmal exocytotic sites, securing that new rounds of exocytosis take place, thus completing the exocytotic process.
Figure 9. Figure 9. Main mechanisms involved in the accumulation of amines and ATP into the CG. A specific vesicular carrier (V‐ATPase) pumps H+ against a concentration and voltage gradient. To reduce the Ψ gradient, Cl− channels open, allowing the pH to drop. The pH gradient is also regulated by Na+ (and probably K+) channels. Protons are used for exchange with CAs (dopamine, DA, or NE) or ATP. The synthesis of NE must occur inside the CG by the enzyme dopamine‐β‐hydroxylase (DBH, light blue) using DA as a substrate. In adrenergic cells, NE must leave the granule to be transformed into EPI in the cytosol (by an enzyme called phenylethanolamine‐N‐methyltransferase, PNMT, not shown) Most solutes bind the granule matrix, thus permitting their accumulation by maintaining the isotonicity of CG versus cytosol. Ca2+ is accumulated and released by a combination of H+/Ca2+ exchange, Ca2+ pump, InsP3‐receptors 683, and ryanodine receptors 552. For clarity, Ca2+ turnover is not shown.
Figure 10. Figure 10. Exocytosis and endocytosis of CGs. (A) For clarity, only one SNARE complex is shown, while some of the accessory proteins are omitted: (1) granule proteins are sorted and packaged into the Golgi apparatus; (2) granules are transported to the release sites by tubulin (not shown); (3) actin filaments drive granules to specific tethering points; (4) “granule docking,” the SNARE complex starts to organize and the granule docks to the plasmalemma; (5) priming, mediated by Munc‐18 and complexin, thus allowing a tighter interaction of SNARE complexes. Munc13 acts on syntaxin changing its conformation, thereby leading to SNARE proteins zippering and the formation of fusion pore; (6) the initial fusion pore allows a limited exchange of water and solutes; (7) fusion pore dilatation allowing the partial or complete release of the granule content; depending on the extent of dilatation and duration of the Ω state, more or fewer solutes will be released. The SNARE complex is disassembled; (8) cavicapture. This partial exocytosis occurs when a dilated, but reversible, fusion pore allows the partial release of small molecules like peptides. Whether these granules can go to the SRP or get exocytosed again is unknown; (9) membrane recovery by endocytosis. Two major mechanisms might be involved: depending on clathrin and dynamin 2 or clathrin‐independent that uses dynamin 1 to promote granule fission. The inner content of the granule rapidly acidifies; (10) clathrin is disassembled and the granule can travel deeper inside the cell toward either endosomes or lysosomes from where they can reenter in the secretory cycle after sorting in the Golgi (11). Note that sizes of the resulted endocytotic granules are now smaller, and granule matrices are clearer as a result of protein loss during exocytosis. Note also that some of the steps are reversible (blue double head arrows). (B) Organization of the SNARE complex in the priming state. The presence of cholesterol and lysophospholipids allows the curvature of the cell membrane. Note the lateral disposition of coiled‐coil of proteins and the proposed situation of Munc‐18 and complexin.
Figure 11. Figure 11. Different pools of granules are involved in the secretory responses. (A) Even in the continuous presence of Ach, the secretion of CA from perfused cat adrenals progressively decays (gray bars). Cumulative CA secretion is superimposed (blue trace). Modified, with permission, from Douglas WW, and Rubin RP, 1961 176. (B) Although the time courses are different, a similar situation occurs when secretion is elicited by rising intracellular Ca2+ in permeabilized CCs (leaky cell). Modified, with permission, from Baker PF, and Knight DE, 1981 44. (C) Recordings of whole‐cell capacitance from mouse CCs evidence the presence of at least two exocytotic kinetics: rapid (RRP) and slow (SRP). Authors tested the effect of rising intracellular Ca2+ by flash photolysis of NP‐EGTA (taken from Figure 2A in Ref. 591). Notice the different time course compared with panels A and B. (D) Newly produced granules are the first to be released. Perfused CCs are stimulated with a nicotinic agonist and CA secretion continuously recording by an electrochemical detector. The analysis of the perfusate shows that EGFP (labeling neuropeptide Y) is released only during the first pulses. Modified, with permission, from Estevez‐Herrera J, et al., 2016 214.
Figure 12. Figure 12. Intracellular signaling pathways and physiology of the chromaffin cell. Acetylcholine and PACAP (sympathetic preganglionic) release from splanchnic nerve activates the nicotinic (AChR) and PACAPergic (PAC1R) receptors, triggering catecholamine and neuropeptide secretion from CG, and increased transcription of genes encoding biosynthetic enzymes for catecholamines (TH, PNMA), and prohormones from which processing to mature neuropeptides occurs, and stimulus‐secretion‐synthesis coupling in the chromaffin cell. PAC1R activation promotes Gs coupling to adenylate cyclase (AC), the elevation of cyclic AMP (cAMP), and the activation of three separate cAMP effectors. Protein kinase A (PKA) mediates CREB‐dependent gene transcription; Epac mediates Rap‐dependent activation of the MAP kinase p38, leading to activation of transcription factors including AP1; NCS‐Rapgef2 mediates Rap‐dependent activation of the mixed‐function kinase B‐Raf, allowing MEK upregulation of the MAP kinase ERK (extracellularly regulated kinase) and gene activation through a combination of transcription factors. Stimulus‐secretion‐synthesis coupling also involves on the intercellular level increased expression of connexins that form gap junctions, which help to amplify chromaffin cell secretion from the adrenal gland as a whole. There is as yet no direct proof for PACAP or acetylcholine as the principal mediator of what might be termed the “gap‐junction response.” IFN, TNF, IL‐1, and IL‐6 effects on cognate receptors on chromaffin cells and cellular sequelae in the chromaffin cell are not shown, but synergize with PACAP stimulation to modulate both catecholamine and peptide secretion and chromaffin cell gene transcription. Splanchnic nerve input affords synergistic as well as antagonistic interactions between cytokines and PACAP under physiological conditions in which both stress and inflammation may play a role. Finally, secretory products of the chromaffin cell itself, including substance P, other neuropeptides, and chromogranin‐derived peptides such as catestatin, modulate chromaffin cell secretion via paracrine actions, in part through modulation of AChR function. See text, and references in text, for further details.
Figure 13. Figure 13. The adrenal medulla as a stress transducer and neuroimmunoinflammatory and cardiovascular regulator. Lower figure. a. The “final common pathway” for stress responding in the CNS is the activation of neurons in the paraventricular nucleus (PVN) of the hypothalamus (Hy), which projects both to the cell bodies of sympathetic preganglionic neurons in the intermediolateral column of the spinal cord and to the median eminence: a′. for ACTH release from the pituitary (Pit) to stimulate corticosterone/cortisol (CORT) release from adrenal cortex; b′. cell bodies in the intermediolateral column of the spinal cord innervate the CCs of the adrenal medulla via the splanchnic nerve, and sympathetic postganglionic nerve targets via para‐ and prevertebral postganglionic sympathetic neurons b. via the splanchnic nerve, releasing ACh basally, and ACh and PACAP during stress, with activation of both secretion by ACh and PACAP, and of CC signaling pathways by PACAP increasing expression of genes encoding neuropeptides (NPs), additional mediators, catecholamine biosynthetic enzymes, and adhesion factors and connexins that increase cell‐cell communication among CCs and amplify CA, neuropeptide, and chromogranin output in response to stress; c. NP (neuropeptide) release from CCs has autocrine effects on CA secretion from CCs themselves (e.g. catestatin, substance P, and others), activation of sensory neurons (e.g. BAM22P, acting on specific receptors expressed in sensory nerves), and modulation of CORT secretion from the adrenal cortex (galanin, VIP, and other peptides), as well as hormonal effects on distant organs; d. CA release from CCs into the general circulation, and affecting metabolism, heart rate, blood pressure, and immune cell mobilization; e. Cytokines released as blood‐borne molecules or locally from circulating monocyte macrophages act as inhibitors of CORT secretion in the adrenal cortex, and as modulators of peptide secretion in adrenal cortex via receptors on CCs themselves; f. Sensory inputs to adrenal medulla sense CC secretory activity via release of BAM‐22P, for which sensory neurons express specific receptors. Also depicted are the targets of glucocorticoid (CORT) release from the adrenal cortex at the pituitary g and immune system g′, the latter decreasing in turn cytokine secretion, which affects adrenomedullary function during stress. For a further explication of the figure, see the text.
Figure 14. Figure 14. Divergent responses of rat CCs to GABAA receptor activation. (A) GABA response is excitatory in immature neurons because of a greater functionality of NKCC1. (B) In mature neurons, GABA response is inhibitory because of the dominant activity of the KCC2. (C) GABAA‐Rs‐mediated response is depolarizing with [Ca2+]i elevation in ∼44% of rat adrenal CCs. (D) in ∼26% of CCs, GABA response is hyperpolarizing and causes [Ca2+]i drop. The scheme also represents the anion‐exchanger AE3 (pendrin), which accumulates Cl− in exchange for intracellular HCO3− and participates in Cl− transport into CCs as a replacement for NKCC1. VDDC: voltage‐dependent Ca2+ channel.
Figure 15. Figure 15. Ryanodine effects on depolarization‐induced CA secretion. (A, B) Burst of amperometric spikes elicited by a 5‐s‐long depolarizing pulse in a WKY (A) and an SHR CCs (B) before (top) and after (bottom) incubation with 10 μM ryanodine. (C, D) Mean cumulative charge in WKY and SHR CCs, respectively, before and after ryanodine treatment. The cumulative charge after RyR blockade was not significantly affected in WKY CCs (20.8 vs. 18.8 pC; p = 0.274), but it was drastically reduced in SHR CCs (from 43.9 to 10.1 pC; p = 0.0001). The number of cells examined is shown in parentheses. Reused, with permission, from Segura‐Chama P, et al., 2015 566.
Figure 16. Figure 16. Cell signaling pathways leading to CACNA1H gene expression and Cav3.2 channels recruitment during chronic or intermittent hypoxia. Schematic pathway of the activation of transcription factors (HIF, CREB, etc.) and CACNA1H gene expression through a NOX, ROS, PLC, and PKC cascade leading to Cav3.2 channels recruitment during chronic/intermittent hypoxia. Adapted, with permission, from Mahapatra S, et al., 2012 417.


Figure 1. Different firing modes of spontaneously active chromaffin cells. (A, B) Spontaneous AP trains recorded from two different rat CCs displaying “irregular” and “regular” tonic firings, respectively. (C) Spontaneous AP trains exhibiting slow‐wave bursting recorded from a mouse CC. Below is shown a single burst at an expanded time scale (dashed rectangle) and the overlap of consecutive APs within a burst. Numbers indicate the sequential position in the burst. Adapted, with permission, from Vandael DH, et al., 2015 633.


Figure 2. Time course of Na+, Ca2+, and K+ currents during slow‐wave bursts in mouse CCs. (A) AP‐clamp experiment measuring Kv and BK currents. Top: AP bursts elicited by current steps were recorded at current‐clamp mode and used as voltage command (black trace) in voltage‐clamp experiments. Bottom: Kv currents are shown in red and BK currents in gray. (B, C) As in (A), but the currents isolated were Ca2+ currents (blue), SK (orange), and Na+ (black). (D) Top: BK, SK, and Kv outward current amplitudes versus the spike number of the burst. Bottom: Same, but for the Na+ and Ca2+ inward currents. Adapted, with permission, from Vandael DH, et al., 2015 633.


Figure 3. Low pHo induces burst firing in mouse CCs. Spontaneous firing (no current injection) recorded in mouse CCs at pHo 7.4, 7.0, and 6.6. Bottom: AP recordings on an expanded time scale corresponding to the gray window above. A decrease in pHo results in resting membrane depolarization and the switch of firing modes from tonic (pHo 7.4) to mildly bursting (pHo 7.0), to sustained bursting (pHo 6.6). Intermittent and sustained burst firing are accompanied by a net decrease of AP peak amplitude associated with the slow inactivation of Nav1.3 channels at depolarized potentials. The dotted line indicates the 0‐mV level. Adapted, with permission, from Guarina L, et al., 2017 260.


Figure 4. Spike frequency adaptation during current injections in mouse CCs. (A) Representative current‐clamp recordings from WT mouse CCs in response to 5, 10, or 15 pA current injection from Vh = −70 mV (from top to bottom). (B) Evolution of the instantaneous firing frequency in WT mouse CCs at 15 pA in control (black squares) and in the presence of the SK channel blocker apamin (200 nM; red circles). (C) AP recordings in the presence of 200 nM apamin during 15 pA current injection, to be compared with the control trace to the left. Adapted, with permission, from Vandael DHF, et al., 2012 635.


Figure 5. Voltage‐dependent modulation of CaV2.1 and CaV2.2 in CCs. (A) Acute application of ATP (50 μM) slows down the activation of N‐ and P/Q‐type Ba2+ currents recorded at 0 mV in a bovine CC (for details, see Ref. 98). (B) The delayed activation of N‐ and P/Q‐type Ba2+ currents induced by the acute application of met‐enkephalin (10 μM; black trace; control) is recovered by a 50‐ms prepulse step depolarization to +70 mV (red dot; red trace) (for details, see Ref. 573). (C) Acute application of the soluble vesicle lysate (SVL) containing (EPI, NE, opioids, and ATP) causes N‐ and P/Q‐type current delayed activation in bovine CCs (for details, see Ref. 10). (D, E) Autocrine inhibition of N‐ and P/Q‐type channels revealed by changing cell superfusion from “stop‐flow” to “flow” condition, in bovine CCs. In the “flow” condition, there is no autocrine inhibition. Ba2+ currents at 0 mV are fast activating. In the “stop‐flow” condition, the autocrine‐released material inhibits through GPCRs the opening of CaV2 (N‐ and P/Q‐type) channels, inducing marked activation delay. Adapted, with permission, from Carabelli V, et al., 1998 98. (F) Ba2+ currents recorded from a cell that is part of a cluster undergo robust autocrine modulation (black trace, control). A prepulse to +100 mV is able to rescue the fast channel activation by removing the autocrine inhibition induced by the neurotransmitters released by the surrounding cells (for details, see Ref. 290).


Figure 6. Up‐ and downmodulation of CaV1.2 and CaV1.3 channels by the cAMP/PKA and NO/cGMP/PKG pathways in mouse CCs. The top half illustrates the molecular components and the sequential steps of the β‐AR‐mediated upregulation of CaV1.2 and CaV1.3 L‐type channels through the activation of adenylate cyclase (AC), leading to cAMP production, activation of PKA, and CaV1 channel phosphorylation, causing an increase in open channel probability. The bottom part shows the molecular components and the sequential steps of the NO‐mediated downregulation of CaV1.2 and CaV1.3 L‐type channels through the activation of a soluble guanylate cyclase (sGC), leading to cGMP production, activation of PKG, and CaV1 channels phosphorylation, causing a decrease in open channel probability. NO is produced by membrane NO‐synthases. cGMP is also produced by a membrane guanylate cyclase (mGC). Adapted, with permission, from Mahapatra S, et al., 2012 417.


Figure 7. Synergistic effects of cAMP/PKA and cGMP/PKG pathways on Cav1 currents of WT mouse CCs. The right side is a schematic representation of CaV1 channel α1 subunit with two hypothetical PKA and PKG phosphorylation sites (P). The schemes represent the situation under basal conditions (middle), a synergistic potentiation (top), and a synergistic inhibition (bottom) of CaV1 channel. PKA and PKG P‐sites are partially phosphorylated (P) or unphosphorylated under resting conditions. Phosphorylation and dephosphorylation drove by up‐ and downregulation of PKA and PKG proceed independently of each other and can reach two extreme conditions. In one case, the two PKA P‐sites are dephosphorylated and the two PKG P‐sites are phosphorylated (minimal CaV1 current; cyan trace, on the top left panel). Alternatively, the PKA sites are phosphorylated and PKG P‐sites are dephosphorylated (maximal CaV1 current; cyan trace, on the bottom left panel). The two panels to the left show the time course of synergistic downregulation of CaV1 channels induced by the sequential application of the PKA inhibitor H‐89 and the PKG activator 8‐pCPT‐cGMP (top) and the synergistic upregulation of CaV1 channels by sequential application of the PKA activator forskolin and PKG inhibitor KT 5823 (bottom). Adapted, with permission, from Mahapatra S, et al., 2012 417; Adapted, with permission, from Vandael DHF, et al., 2013 634 (drawing and experimental data).


Figure 8. The concept of functional triads that regulate the generation of local [Ca2+]c transients and exocytosis responses upon stimulation of CCs. (1) After cell depolarization with the physiological neurotransmitter ACh, the voltage‐dependent Ca2+ channels open. (2) Ca2+ enters the cell through a huge electrochemical gradient, giving rise to the formation of a high‐Ca2+ microdomain (HCMD) of about 10 μM or higher near the sub‐plasmalemmal exocytotic sites. (3) High Ca2+ is required to trigger the fast exocytotic release of CAs. (4) The HCMD quickly dissipates initially by mobile Ca2+ buffers (not drawn) and more slowly by Ca2+ uptake by the ER Ca2+‐ATPase (SERCA). (5) The second more relevant pathway for the clearance of the [Ca2+]c transient is the mitochondrial Ca2+ uniporter, which has a low‐affinity high‐capacity for Ca2+ sequestration into the mitochondrial matrix. (6, 7) In both ER and mitochondria (Mito), the matrix [Ca2+]c can reach near half a millimolar. ER Ca2+ can be released back into the cytosol through a CICR mechanism via ryanodine receptors, lnsP3 receptors (6), or through the mitochondrial Na+/Ca2+ exchanger (7). (8) Ca2+ diffusion serves to redistribute Ca2+ at inner areas of the cell core to generate low‐Ca2+ microdomains (LCMD) of around half micromolar that are required for the cytoskeleton‐mediated Ca2+‐dependent vesicle traffic. (9) The Ca2+ levels of the LCMD refills with new vesicles the RRP at sub‐plasmalemmal exocytotic sites, securing that new rounds of exocytosis take place, thus completing the exocytotic process.


Figure 9. Main mechanisms involved in the accumulation of amines and ATP into the CG. A specific vesicular carrier (V‐ATPase) pumps H+ against a concentration and voltage gradient. To reduce the Ψ gradient, Cl− channels open, allowing the pH to drop. The pH gradient is also regulated by Na+ (and probably K+) channels. Protons are used for exchange with CAs (dopamine, DA, or NE) or ATP. The synthesis of NE must occur inside the CG by the enzyme dopamine‐β‐hydroxylase (DBH, light blue) using DA as a substrate. In adrenergic cells, NE must leave the granule to be transformed into EPI in the cytosol (by an enzyme called phenylethanolamine‐N‐methyltransferase, PNMT, not shown) Most solutes bind the granule matrix, thus permitting their accumulation by maintaining the isotonicity of CG versus cytosol. Ca2+ is accumulated and released by a combination of H+/Ca2+ exchange, Ca2+ pump, InsP3‐receptors 683, and ryanodine receptors 552. For clarity, Ca2+ turnover is not shown.


Figure 10. Exocytosis and endocytosis of CGs. (A) For clarity, only one SNARE complex is shown, while some of the accessory proteins are omitted: (1) granule proteins are sorted and packaged into the Golgi apparatus; (2) granules are transported to the release sites by tubulin (not shown); (3) actin filaments drive granules to specific tethering points; (4) “granule docking,” the SNARE complex starts to organize and the granule docks to the plasmalemma; (5) priming, mediated by Munc‐18 and complexin, thus allowing a tighter interaction of SNARE complexes. Munc13 acts on syntaxin changing its conformation, thereby leading to SNARE proteins zippering and the formation of fusion pore; (6) the initial fusion pore allows a limited exchange of water and solutes; (7) fusion pore dilatation allowing the partial or complete release of the granule content; depending on the extent of dilatation and duration of the Ω state, more or fewer solutes will be released. The SNARE complex is disassembled; (8) cavicapture. This partial exocytosis occurs when a dilated, but reversible, fusion pore allows the partial release of small molecules like peptides. Whether these granules can go to the SRP or get exocytosed again is unknown; (9) membrane recovery by endocytosis. Two major mechanisms might be involved: depending on clathrin and dynamin 2 or clathrin‐independent that uses dynamin 1 to promote granule fission. The inner content of the granule rapidly acidifies; (10) clathrin is disassembled and the granule can travel deeper inside the cell toward either endosomes or lysosomes from where they can reenter in the secretory cycle after sorting in the Golgi (11). Note that sizes of the resulted endocytotic granules are now smaller, and granule matrices are clearer as a result of protein loss during exocytosis. Note also that some of the steps are reversible (blue double head arrows). (B) Organization of the SNARE complex in the priming state. The presence of cholesterol and lysophospholipids allows the curvature of the cell membrane. Note the lateral disposition of coiled‐coil of proteins and the proposed situation of Munc‐18 and complexin.


Figure 11. Different pools of granules are involved in the secretory responses. (A) Even in the continuous presence of Ach, the secretion of CA from perfused cat adrenals progressively decays (gray bars). Cumulative CA secretion is superimposed (blue trace). Modified, with permission, from Douglas WW, and Rubin RP, 1961 176. (B) Although the time courses are different, a similar situation occurs when secretion is elicited by rising intracellular Ca2+ in permeabilized CCs (leaky cell). Modified, with permission, from Baker PF, and Knight DE, 1981 44. (C) Recordings of whole‐cell capacitance from mouse CCs evidence the presence of at least two exocytotic kinetics: rapid (RRP) and slow (SRP). Authors tested the effect of rising intracellular Ca2+ by flash photolysis of NP‐EGTA (taken from Figure 2A in Ref. 591). Notice the different time course compared with panels A and B. (D) Newly produced granules are the first to be released. Perfused CCs are stimulated with a nicotinic agonist and CA secretion continuously recording by an electrochemical detector. The analysis of the perfusate shows that EGFP (labeling neuropeptide Y) is released only during the first pulses. Modified, with permission, from Estevez‐Herrera J, et al., 2016 214.


Figure 12. Intracellular signaling pathways and physiology of the chromaffin cell. Acetylcholine and PACAP (sympathetic preganglionic) release from splanchnic nerve activates the nicotinic (AChR) and PACAPergic (PAC1R) receptors, triggering catecholamine and neuropeptide secretion from CG, and increased transcription of genes encoding biosynthetic enzymes for catecholamines (TH, PNMA), and prohormones from which processing to mature neuropeptides occurs, and stimulus‐secretion‐synthesis coupling in the chromaffin cell. PAC1R activation promotes Gs coupling to adenylate cyclase (AC), the elevation of cyclic AMP (cAMP), and the activation of three separate cAMP effectors. Protein kinase A (PKA) mediates CREB‐dependent gene transcription; Epac mediates Rap‐dependent activation of the MAP kinase p38, leading to activation of transcription factors including AP1; NCS‐Rapgef2 mediates Rap‐dependent activation of the mixed‐function kinase B‐Raf, allowing MEK upregulation of the MAP kinase ERK (extracellularly regulated kinase) and gene activation through a combination of transcription factors. Stimulus‐secretion‐synthesis coupling also involves on the intercellular level increased expression of connexins that form gap junctions, which help to amplify chromaffin cell secretion from the adrenal gland as a whole. There is as yet no direct proof for PACAP or acetylcholine as the principal mediator of what might be termed the “gap‐junction response.” IFN, TNF, IL‐1, and IL‐6 effects on cognate receptors on chromaffin cells and cellular sequelae in the chromaffin cell are not shown, but synergize with PACAP stimulation to modulate both catecholamine and peptide secretion and chromaffin cell gene transcription. Splanchnic nerve input affords synergistic as well as antagonistic interactions between cytokines and PACAP under physiological conditions in which both stress and inflammation may play a role. Finally, secretory products of the chromaffin cell itself, including substance P, other neuropeptides, and chromogranin‐derived peptides such as catestatin, modulate chromaffin cell secretion via paracrine actions, in part through modulation of AChR function. See text, and references in text, for further details.


Figure 13. The adrenal medulla as a stress transducer and neuroimmunoinflammatory and cardiovascular regulator. Lower figure. a. The “final common pathway” for stress responding in the CNS is the activation of neurons in the paraventricular nucleus (PVN) of the hypothalamus (Hy), which projects both to the cell bodies of sympathetic preganglionic neurons in the intermediolateral column of the spinal cord and to the median eminence: a′. for ACTH release from the pituitary (Pit) to stimulate corticosterone/cortisol (CORT) release from adrenal cortex; b′. cell bodies in the intermediolateral column of the spinal cord innervate the CCs of the adrenal medulla via the splanchnic nerve, and sympathetic postganglionic nerve targets via para‐ and prevertebral postganglionic sympathetic neurons b. via the splanchnic nerve, releasing ACh basally, and ACh and PACAP during stress, with activation of both secretion by ACh and PACAP, and of CC signaling pathways by PACAP increasing expression of genes encoding neuropeptides (NPs), additional mediators, catecholamine biosynthetic enzymes, and adhesion factors and connexins that increase cell‐cell communication among CCs and amplify CA, neuropeptide, and chromogranin output in response to stress; c. NP (neuropeptide) release from CCs has autocrine effects on CA secretion from CCs themselves (e.g. catestatin, substance P, and others), activation of sensory neurons (e.g. BAM22P, acting on specific receptors expressed in sensory nerves), and modulation of CORT secretion from the adrenal cortex (galanin, VIP, and other peptides), as well as hormonal effects on distant organs; d. CA release from CCs into the general circulation, and affecting metabolism, heart rate, blood pressure, and immune cell mobilization; e. Cytokines released as blood‐borne molecules or locally from circulating monocyte macrophages act as inhibitors of CORT secretion in the adrenal cortex, and as modulators of peptide secretion in adrenal cortex via receptors on CCs themselves; f. Sensory inputs to adrenal medulla sense CC secretory activity via release of BAM‐22P, for which sensory neurons express specific receptors. Also depicted are the targets of glucocorticoid (CORT) release from the adrenal cortex at the pituitary g and immune system g′, the latter decreasing in turn cytokine secretion, which affects adrenomedullary function during stress. For a further explication of the figure, see the text.


Figure 14. Divergent responses of rat CCs to GABAA receptor activation. (A) GABA response is excitatory in immature neurons because of a greater functionality of NKCC1. (B) In mature neurons, GABA response is inhibitory because of the dominant activity of the KCC2. (C) GABAA‐Rs‐mediated response is depolarizing with [Ca2+]i elevation in ∼44% of rat adrenal CCs. (D) in ∼26% of CCs, GABA response is hyperpolarizing and causes [Ca2+]i drop. The scheme also represents the anion‐exchanger AE3 (pendrin), which accumulates Cl− in exchange for intracellular HCO3− and participates in Cl− transport into CCs as a replacement for NKCC1. VDDC: voltage‐dependent Ca2+ channel.


Figure 15. Ryanodine effects on depolarization‐induced CA secretion. (A, B) Burst of amperometric spikes elicited by a 5‐s‐long depolarizing pulse in a WKY (A) and an SHR CCs (B) before (top) and after (bottom) incubation with 10 μM ryanodine. (C, D) Mean cumulative charge in WKY and SHR CCs, respectively, before and after ryanodine treatment. The cumulative charge after RyR blockade was not significantly affected in WKY CCs (20.8 vs. 18.8 pC; p = 0.274), but it was drastically reduced in SHR CCs (from 43.9 to 10.1 pC; p = 0.0001). The number of cells examined is shown in parentheses. Reused, with permission, from Segura‐Chama P, et al., 2015 566.


Figure 16. Cell signaling pathways leading to CACNA1H gene expression and Cav3.2 channels recruitment during chronic or intermittent hypoxia. Schematic pathway of the activation of transcription factors (HIF, CREB, etc.) and CACNA1H gene expression through a NOX, ROS, PLC, and PKC cascade leading to Cav3.2 channels recruitment during chronic/intermittent hypoxia. Adapted, with permission, from Mahapatra S, et al., 2012 417.
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Teaching Material

E. Carbone, R. Borges, L. E. Eiden, A. G. García, A. Hernández-Cruz. Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease. Compr Physiol 9: 2019, 1443-1502.

Didactic Synopsis

Major Teaching Points:

  • During stressful conflicts, chromaffin cells from the adrenal medulla release a surge of catecholamines (epinephrine and norepinephrine) into the bloodstream, which serves to prepare the different organs of the body for the fight-or-flight response, to escape from danger and survive.
  • The secretory response of chromaffin cells is triggered by a rapid elevation of the Ca2+ concentration in the cytosol, mainly contributed by Ca2+ entry via voltage-activated Ca2+ channels that open upon membrane depolarization as a consequence of the activation of postsynaptic cholinergic receptors by the neurotransmitter acetylcholine that is released from splanchnic nerve terminals (neurogenic control).
  • Chromaffin cells express a wide number of Na+, Ca2+, and K+ channels that are also able to generate spontaneous “neuronal-like” tonic and burst-firing patterns that can drive a sustained “nonneurogenic” release of catecholamines under different secretagogues stimulation.
  • The Ca2+ signal due to Ca2+ entry is subsequently modulated by Ca2+ uptake and release in mitochondria and endoplasmic reticulum. Intracellular Ca2+ controls granule movement to the plasma membrane, exocytosis and endocytosis, and couples cell activity to ATP generation.
  • Catecholamines, chromogranins, ATP, GABA, opioids, and other peptides are tightly packaged in secretory granules that release their contents by fusion with the plasmalemma. In this process (exocytosis) intervene several SNARE proteins that regulate the formation of a membrane fusion pore and its subsequent expansion to release the granule content.
  • Catecholamines are preferentially released from newly synthetized granules. Older granules may act as catecholamine donors for favoring their reload.
  • Secretagogues of the adrenal medulla stimulate both catecholamine/peptide synthesis and release via “stimulus-secretion-synthesis coupling.” Chromaffin cell excitability, Ca2+ channel currents, and the ensuing secretory responses are regulated further by several receptors for opioids, PACAP, ATP, GABA, and various other neurotransmitters.
  • Altered cell excitability, Ca2+ handling, and exocytosis defects have been reported in chromaffin cells from rodent models of diseases such as hypertension, Alzheimer’s disease, Huntington’s disease, autism, and amyotrophic lateral sclerosis, suggesting that the defective proteins of the disease also have an impact on chromaffin cell function.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1 Adrenal chromaffin cells behave electrically like neurons. As central and peripheral neurons, chromaffin cells generate spontaneous “all-or-none” action potentials repeated at variable frequency. They either occur as “regular ”or “irregular” trains of single APs (tonic firing) or in rapid sequence followed by long periods of inactivity (burst firing).

Figure 2 Chromaffin cells can fire action potentials in “bursts.” This is the result of an equilibrium between inward (Na+ and Ca2+) and outward (K+) ions passing currents through the cell membrane. Among the inward components, Ca2+ currents are the most important. They sustain the burst up to the last AP, while Na+ currents inactivate quickly. Among the three outward current components (Kv, SK, and BK), the SK is the only K+ current increasing during each AP within the burst. When SK is sufficiently large, it ends the burst by generating the repolarization phase.

Figure 3 Chromaffin cells are sensitive to pH changes. When the extracellular pH lowers, CCs depolarize, increase their firing frequency, and switch their firing from tonic to bursts. This increases Ca2+ entry into the cell and stimulates catecholamine release. Our body uses this CC chemosensory response to compensate blood acidification and hyperkalemia during extreme muscle exercise.

Figure 4 Understanding the electrical properties of CCs. This requires test protocols to determine the ability of the cell to generate trains of APs. In response to square current stimulation pulses, CCs fire trains of APs that fatigue (adapt) with time. The same occurs in central and peripheral neurons. Under control condition mouse CCs, APs have high frequency (16 Hz) at the beginning of the stimulus and adapt to a lower frequency at the end (4 Hz). Blockade of SK channels with apamin (panel c) changes the steady-state adaptation to a frequency of about 8 Hz (red curve in b).

Figure 5 Control of CA secretion by autocrine inhibition. CCs have a potent autocrine feedback inhibition that involves Ca2+ channels. N- and P/Q-type Ca2+ currents activate slowly when cells are perfused with endogenous ATP (panel A), the opioid met-enkephalin (panel B), or a soluble mixture (SLV) containing EPI, NE, ATP, and opioids purified from the secretory granules (panel C). The same slow activation is observed when the perfusion with external solution is stopped (panel E) or when the recorded CC is in a cell cluster (F). In both cases, the unwashed materials released inhibit the Ca2+ currents autocrinally. The slow Ca2+ current activation can be speeded up when the cell is depolarized with a prepulse to +100 mV, which rescues the fast channel activation (B and F).

Figure 6 Opposing modulation by cAMP/PKA and cGMP/PKG pathways on L-type Ca2+ channels. The top half; ß-AR mediated upregulation of CaV1.2 and CaV1.3 Ca2+ channels through the following sequence: AC activation, cAMP production, PKA activation, CaV1 channel phosphorylation, and increase in open channel probability. The bottom half: NO mediated downregulation of L-type Ca2+ channels through the following sequence: soluble guanylate cyclase (sGC) activation, cGMP production, PKG activation, CaV1 channel phosphorylation in a different site, cause a decrease in open channel probability. The consequence is that a modulator acting on either one of the two pathways is potentially able to increase or decrease the L-type Ca2+ currents that are responsible of AP firing and secretory activity of adrenal CCs.

Figure 7 Synergistic action of the cAMP/PKA and cGMP/PKG pathways on L-type Ca2+ channels. When the selective PKG inhibitor KT 5823 blocks the inhibitory effects of PKG and PKA is activated by forskolin (trace b in the left-bottom panel), a strong increase of the L-type Ca2+ current amplitude is induced, which drives burst firing and massive release of catecholamines. The opposite effect occurs when PKG is upregulated by the PKG activator 8-pCPT-cGMP and the PKA activity is reduced by the inhibitor H-89 blocks (trace b in the left-top panel).

Figure 8 Functional triads regulate local [Ca2+]i transients and exocytosis upon CCs stimulation. After cell depolarization by the neurotransmitter ACh, the voltage-dependent Ca2+ channels open (1). Ca2+ enters the cell, forming high-Ca2+ concentration microdomains (HCMD) of 10 µM or higher, near subplasmalemmal exocytotic sites (2). This high Ca2+ is required to trigger the fast exocytotic release of CAs (3). Ca2+ channels close, and HCMD quickly dissipates by mobile Ca2+ buffers, Ca2+ uptake by the ER Ca2+-ATPase (SERCA) (4) and Ca2+sequestration into the mitochondrial matrix by the Ca2+ uniporter (5). Inside both ER and mitochondria (Mito) matrix, [Ca2+] can reach about half a millimolar. Ca2+ can then be released back into the cytosol through the CICR mechanism via ryanodine receptors or lnsP3 receptors of the ER (6) or through the mitochondrial Na+/Ca2+ exchanger (7). Ca2+ diffusion redistributes Ca2+ at inner areas of the cell to generate low-Ca2+ microdomains (LCMD) of around half micromolar (8) that are required for the cytoskeleton-mediated Ca2+-dependent vesicle traffic and the refilling of RRP with new vesicles near subplasmalemmal exocytotic sites (9), securing new rounds of exocytosis.

Figure 9 The acidification is crucial for the accumulation of amines, ATP, and Ca2+ into the CG. A specific vesicular pump (V-ATPase) pumps H+ into the vesicle. To compensate the ?? gradient created by H+ pumping, Cl- channels open, allowing Cl- influx. Protons are used for accumulation by exchanging with catecholamines, Ca2+ or ATP. Dopamine is converted in NE inside the CG by the enzyme dopamine-?-hydroxylase (D???. In adrenergic cells, NE will be further transformed to EPI in the cytosol. Solutes are largely bound to the granule matrix, thus reducing the osmotic force caused by their elevated concentration.

Figure 10 Cycle of exocytosis and endocytosis of CGs. (A) For clarity, only one SNARE complex is shown, while some of the accessory proteins are omitted. 1: granule proteins are sorted and packaged into the Golgi apparatus. 2: granules are transported to the release sites. 3: actin filaments drive granules to specific tethering points. 4: “granule docking” to the membrane. 5: “priming,” both CG- and cell-membrane interact strongly by SNARE complexes, which promote the formation of the fusion pore. 6: the initial fusion pore allows limited exchange of water and solutes. 7: the extent of dilatation and duration of the O state regulate the amount of solutes released. The SNARE complex is disassembled. 8: partial exocytosis occurs when a dilated, but reversible, fusion pore allows the release of small molecules like peptides. 9: membrane recovery by endocytosis will either depend on clathrin and dynamin 2 or on a clathrin-independent mechanism mediated by dynamin 1. Granule rapidly acidifies. 10, 11: after clathrin disassembly, the granule travels deeper inside the cell toward either endosomes or lysosomes. Some of these steps are reversible (blue double head arrows). (B) Detail of the organization of the SNARE complex in the priming state.

Figure 11 Different pools of granules are involved in CA secretion. Even in the continuous presence of high concentrations of ACh, the secretion of CA for time unit in perfused cat adrenals progressively decays (A; gray bars). Something similar occurs when secretion is elicited by elevation of intracellular Ca2+ in permeabilized CCs (B). Exocytotic kinetics observed by cell capacitance measurements reveals at least two components, corresponding to the dynamic release of CGs pools (RRP and SRP; C). When perfused CCs are stimulated by pulses or agonist and CA secretion is continuously monitored by electrochemical detection, the release of CGs containing EGFP-labeled neuropeptide Y is found only during the first tree pulses, implying that newly produced CGs are the first to be released.

Figure 12 Signaling pathways of chromaffin cells. Acetylcholine (ACh) and PACAP are the transmitters controlling the release of catecholamines via splanchnic nerve stimulation in basal (ACh) and stimulated conditions (PACAP and ACh). These transmitters control not only the release of catecholamines and bioactive peptides from chromaffin cells, but also chromaffin cell gene expression that allows compensatory repletion of these molecules in chromaffin cells after they have been depleted by secretion. Both calcium and cAMP signaling control these processes (collectively called stimulus-secretion-synthesis coupling). In addition, circulating first messengers such as cytokines (IL-6 and TNF) and autocoids (such as histamine), through receptors on chromaffin cells, synergize with the splanchnic nerve secretagogues (e.g. PACAP) to amplify chromaffin cell secretion in response to inflammation. Stimulus-secretion-synthesis coupling also involves expression of connexins, molecules expressed on chromaffin cell membranes that further integrate, amplify, and coordinate whole-organ catecholamine secretion.

Figure 13 The adrenal medulla is an integrator of several inputs. CCs acts as a stress transducer and neuroimmunoinflammatory and cardiovascular regulator by integrating inputs from the first messengers mentioned in Figure 12, and providing secreted molecules that modulate the hormonal output of the adrenal cortex (e.g. glucocorticoids) to provide a mode of bidirectional communication to adjust secreted biomolecule activity across a broad range of organismic states, including stress, inflammation, and altered metabolic rate.

Figure 14 GABAA receptor can be excitatory or inhibitory in rat CCs. In immature neurons, GABA response is excitatory because NKCC1 is more active (A), while in mature neurons, GABA response is inhibitory because KCC2 is the dominant transporter (B). In ~44% of rat CCs, a GABAA agonist depolarizes and elevates [Ca2+]i (C), while it hyperpolarizes and causes a [Ca2+]i drop in ~26% of CCs (D). The scheme shows the anion-exchanger AE3 (pendrin), which accumulates Cl- in exchange for intracellular HCO3- and participates in Cl- transport into CCs. VDDC: voltage-dependent Ca2+ channel.

Figure 15 Ryanodine discloses an enhancement of CICR that underlies augmented CA secretion in CCs from hypertensive rats. Ryanodine, a potent blocker of RyRs, diminishes the amount of amperometric spikes elicited by a depolarizing pulse both in normotensive WKY (a) and hypertensive SHR CCs (b). The cumulative charge after RyR blockade is more significantly affected in SHR CCs (d) than in WKY CCs (c).Taken, with permission, from ref (566).

Figure 16 Chromaffin cells are sensitive to chronic and intermittent hypoxia.CCs respond to chronic hypoxia conditions by upregulating the usually unexpressed Cav3.2 (T-type) Ca2+ channels that regulate the release of neurotransmitters (EPI, NE, ATP, and opioids) at rather negative voltages (-50 mV; low threshold). This occurs through the activation of NOX2/NOX4, ROS, PLC, PKC, and the nuclear transcription factor HIF that leads to CACNA1H gene expression.

 


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Article Title: Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease
 

How to Cite

Emilio Carbone, Ricardo Borges, Lee E. Eiden, Antonio G. García, Arturo Hernández‐Cruz. Chromaffin Cells of the Adrenal Medulla: Physiology, Pharmacology, and Disease. Compr Physiol 2019, 9: 1443-1502. doi: 10.1002/cphy.c190003