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Gap Junctions in the Cardiovascular System

David C. Spray, Sylvia O. Suadicani, Miduturu Srinivas, David E. Gutstein, Glenn I. Fishman

10.1002/cphy.cp020104

Source: Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart

Originally published: 2002

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Cardiovascular Gap Junction Proteins
1.1 Ultrastructural Features
1.2 Higher Resolution Through Projection Images
1.3 The Connexin Multigene Family
1.4 Connexin and Connexon Topology
1.5 Regional Connexin Expression in the Cardiovascular System
1.6 Why Are There Multiple Cardiovascular Connexins?
2 Macroscopic Organization of the Heart (Cables, Bricks, and Textures)
2.1 Gap Junction Organization within the Tissue
2.2 Modeling Tissue Connections
2.3 Optical Imaging of Patterned Cell Cultures
2.4 Microscopic and Macroscopic Discontinuities
3 Regulation of Gap Junction Expression, Formation, and Degradation
3.1 Life and Death of Gap Junctions
3.2 Long‐Term Changes in Gap Junction Expression
3.3 Transcriptional Regulation of Cardiac Gap Junction Genes
4 Functional Properties of Cardiovascular Gap Junctions
4.1 Cardiovascular Gap Junctions Are K+, Ca2+, and Second Messenger Channels
4.2 Biophysical Properties of Junctional Channels
4.3 Gating of Gap Junctional Channels by Transjunctional Voltage
4.4 Properties of Specific Connexins Expressed in Exogenous Systems
4.5 Properties of Gap Junctions Evaluated in Cardiovascular Cells
4.6 Gating of Gap Junctions by Other Stimuli
5 Genetic and Somatic Disease States in Which Gap Junction Expression or Function is Altered
5.1 Somatic Cardiac Abnormalities
5.2 Reversed Physiology: Inferring Gene Function from Its Absence in Knockout Mice
Figure 1. Figure 1.

Ultrastructural features of cardiac gap junctions: From thin section (A,B) and freeze‐fracture (C) electron microscopy to negatively stained isolated junctional membranes (D) and projection density maps (E, F) of gap junctions. A: Transmission electron micrographs of canine myocardium showing the distribution of gap junctions at the intercalated disk. Top panel: The sarcomeric Z‐line (Z) and the junctions within plicate (P, open arrow) and interplicate segments (solid arrow) are evident in this longitudinal section of the myocyte showing typical undulating geometry. Bottom panel: Undulations of apposed junctional membranes are also observed in a transverse section that emphasizes the long dimension of an interplicate gap junction. B: Higher power electron micrograph of gap junction between rat ventricular myocytes showing the characteristic seven‐layered structure and the conspicuous fuzzy coating at both cytoplasmic surfaces. Fixed by vascular perfusion with osmium tetroxide and stained with uranyl acetate and lead citrate (magnification 156 × 103). C: Electron micrograph of replica of freeze‐fractured gap junction between rat ventricular myocytes. Fixed by vascular perfusion with glutaraldehyde and unidirectionally shadowed with platinum‐carbon. The particulate P‐face and the pitted E‐face of the junction are seen on the top and bottom sides of the picture, respectively (magnification 134 × 103). D: In an en face view of junctional membranes isolated from rat ventricle, the hexagonal structure of the connexons are outlined by phosphotungstate deposition around and within the core of the intercellular channels (magnification 241 × 103). E and F: Projection density maps of rat cardiac gap junction obtained at 1.5 nm resolution (E), showing individual hexameric connexons, and at 0.7 nm resolution (F), showing symmetrical circular densities that are interpreted as helices lining the channels, α helices that are most exposed to lipids (arrow) and two continuous dense bands that presumably represent the other two transmembrane α‐helices. Spacing between grid bars is 4 nm.

From Manjunath et al. with permission 153. From Page and Manjunath with permission 188. From Page and Manjunath with permission from reference 188). From Luke and Saffitz, 150, with permission. From Yeager and Nicholson 307 with permission
Figure 2. Figure 2.

Gap junction channels (A) are formed of hemichannels or connexons composed of connexin proteins (B) encoded by connexin genes (C). A: Schematic drawing of gap junction structure deduced from the classical study applying X‐ray diffraction to gap junctions isolated from mouse liver 152. Two connexons dock across extracellular space to form the complete gap junction channel. B: The connexin protein and its membrane topology: the two extracellular loops (C1 and C2), the four transmembrane domains (M1, M2, M3, and M4), the intracellular loop (CL, short in group I or α subfamily and long in group II or β connexin subfamily), and the cytoplasmic amino‐ and carboxyl‐terminal domains (NT and CT). C, top: Connexin gene (exons E1 and E2, intron IVS). C, bottom: Connexin transcript. Transmembrane domains of encoded protein indicated by dark bars.
Figure 3. Figure 3.

Schematic diagram illustrating general pattern of distribution and relative abundance of connexin types expressed in different regions of the mammalian heart and vessel wall.
Figure 4. Figure 4.

Pattern of connexin 43 (Cx43) and desmin distribution during the developmental differentiation of mouse ventricle myocytes as viewed by double immunofluorescence. A: Cross‐sections of newborn mouse ventricular wall showing desmin striations (identifying Z‐lines of myofibrils) and the homogenous distribution of Cx43 between the myocytes. B: Longitudinal sections of two‐week‐old mouse ventricular wall showing the intercalated disks, which are strongly immunoreactive to anti‐desmin antibodies (white arrows) and the initiation of polarized Cx43 expression that progressively becomes restricted to the opposite ends of the myocytes (intercalated disks, white arrows) and to the adjacent lateral regions. C: Longitudinal sections of three‐week‐old mouse ventricular wall showing the even more pronounced polarization of Cx43 expression at the intercalated disks (white arrows) that was first evident at two weeks postpartum. D: Longitudinal section of adult mouse ventricular wall showing that Cx43 expression is now confined to the intercalated disks. This pattern of expression is observed at the conclusion of myocyte differentiation and characterizes myocytes in adult ventricular tissue (bars = 50 μm).

From Fromaget et al. 81 with permission
Figure 5. Figure 5.

Expression patterns of Cx43 (top panels), Cx45 (middle panels), and Cx40 (bottom panels) in the crista terminalis (left panels) and left ventricular muscle (right panels) viewed by immunofluorescence. In the crista terminalis, the distribution of immunoreactivity for the three connexins follows a regular and simple pattern, consistent with the localization of the intercalated disks at the true ends of the atrial myocytes. In the ventricle, the pattern is more complex with side‐to‐side as well as end‐to‐end staining, consistent with the more extensive intercellular junctions that occur between ventricular myocytes.

From Saffitz et al. 219
Figure 6. Figure 6.

Effect of gap junctions on longitudinal (left panels) and transverse propagation (right panels) in a 2D cellular network model. A: Spatial distribution of the depolarization (Vm) for longitudinal (left) and transverse (right) conduction. Bold lines represent changes of Vm within cells; dashed lines represent the step changes in Vm at the gap junctions. Note that time scale on the right is longer, so that signal is more rapidly attenuated (and discrete Vm drops at borders more profound) for transverse conduction. B: Time course of activation within a network of five myocytes (labeled a–e) in the 2D model, arranged longitudinally (left) or transversely (right). C: Excitation isochrones (separated by 4 μsec on the left and 3 μsec on the right) along the longitudinal (left) and transverse (right) axes of the myocytes. Direction of propagation is indicated by arrows.

From Spach and Heidlage, 235
Figure 7. Figure 7.

Regulation of gap junction expression and degradation. A: Diagram of the life cycle of cardiac gap junctions. 1. MRNA is transcribed in the nucleus and translocated to the cytoplasm; 2. Protein is translated and inserted into the Endoplasmic reticulum. Mis‐translated or mis‐folded protein is proteolyzed by the Proteasome . Along the way from ER to Golgi , connexons are formed by connexin oligomerization. The connexons are then transported to the cell surface where they meet and dock and with connexons of adjacent cells to form gap junction channels. Removal of gap junctions is through both proteasomal and lysosomal pathways . B: Transcriptional activity of human connexin43‐luciferase chimeric plasmids transfected into rat cardiac myocytes in vitro and adult rat ventricle myocytes in vivo. On the right, diagrams of the reporter gene constructs with nested deletions from the human Cx43 gene (−2400 to −50 base pairs, relative to transcription initiation). On the left, plot of relative luciferase activity generated by each construct, showing that the presence of at least 175 base pairs of 5′‐flanking sequence is required for measurable transcription. Differences in transcription in in vitro and in vivo experiments was only seen with the 2400 base pair construct. In vivo this construct was 170‐fold more active than the −50Cx43Lux plasmid, while in vitro it was only 30‐fold more active. Each data point represents the mean ± S. E. from three to five different animals. Results in vivo are compared to myocytes in vitro by arbitrarily setting the −250Cx43Lux construct value to 1 for both systems.

Modified from Laing et al. 133. Modified from De Leon et al. 153, with permission
Figure 8. Figure 8.

Model for slow intercellular calcium wave propagation proposed by Sanderson and colleagues 221. Mechanical stimulation of a single cell in culture can induce the activation of phospholipase C (PLC) and synthesis of inositol trisphosphate (IP3), thereby activating IP3 receptors (IP3R) to release calcium from intracellular stores. The diffusion of IP3 to the neighboring cells, passing through gap junction channels, triggers the propagation of calcium waves from cell to cell. An extracellular pathway can also operate in parallel with the intercellular pathway. In this case, an extracellular messenger released from the stimulated cell diffuses from cell to cell and communicates the signal through activation of membrane receptors. In most cells that exhibit this mechanism, ATP has proven to be the extracellular messenger mediating the propagation of the calcium waves through activation of purinoceptors.
Figure 9. Figure 9.

Triggered propagated contraction (TPC) in rat trabeculae. The constant interval between the peak of sarcomere shortening (vertical dotted lines) recorded simultaneously at five different points (300 μm apart) along the trabeculae (length 2.9 mm) during a TPC indicates that the contraction propagates with a constant velocity (1.4 mm/sec) along the preparation. SL = sarcomere length; F = force of contraction.

From ter Keurs and Zhang, 267, with permission
Figure 10. Figure 10.

Dependence of junctional conductance of Cx40, Cx43, and Cx45 gap junction channels on transjunctional voltage (Vj). A: Recordings of junctional current (Ij, lower traces) measured in one cell of a pair expressing each connexin individually in response to 8–15 sec long pulses from 0 to ± 80 mV (in 20 mV increments) that were applied to the other cell. Junctional currents were maximal at the beginning of the pulses and declined to steady‐state values in a time‐ and voltage‐dependent manner. B: Relationship between Vj and steady‐state junctional conductance of Cx40, Cx43, and Cx45 gap junction channels (solid lines) and of Cx37 and Cx50 (dotted lines). The lines are a fit of the normalized steady‐state junctional conductance (Gj, the ratio of the steady‐state gj to maximal gj)‐Vj relationship to a two state Boltzmann equation. The Boltzmann parameters for channels formed by each connexin type are listed in Table 2.
Figure 11. Figure 11.

Unitary conductances of gap junction channels formed by Cx40 (A), Cx43 (B), and Cx45 (C) measured with pipettes containing 130 mM CsCl. A: Top. Junctional currents measured in one cell of a Cx40‐transfected N2A cell pair in response to 16 sec voltage step to 30 mV from a holding potential of 0 mV that was applied to the other cell. Single Cx40 channels were maximally open (O) from the baseline level (C) immediately upon application of a voltage pulse. The amplitude of the unitary current measured from all points amplitude histogram was 5.8 pA, corresponding to a single‐channel conductance of 193 pS. A: Bottom. Single‐channel current voltage (Ij‐Vi) relationships of the junctional current constructed from responses of Cx40‐transfected N2A cells to a series of ramps from −100 to +100 mV. The unitary conductance of the main state (γj, main) and the substate (γj, sub), measured as the slopes of the current‐voltage relationships (solid lines), were 170 pS and 40 pS, respectively. The ratio of γj, sub and γj, main for Cx40 channels is similar to the gmin/gmax value obtained from macroscopic recordings. B, C: Single‐channel currents from Cx43‐ and Cx45‐transfected cell pairs at voltages close to the respective Vi values obtained from macroscopic recordings. B: Single‐channel current through Cx43 gap junction channels predominantly exhibits transitions between a subconductance state (S) and the open state (O) at a Vj of 75 mV. Transitions to the baseline level (C) were rare; only one such transition was observed during the 40‐second pulse. Unitary conductances of the fully open state and the subconductance state were 80 pS and 26 pS, respectively. C: transitions of single‐channel current from a Cx45‐transfected cell pair at a Vj of 30 mV to the subconductance state is not clearly detected due to the small unitary conductance of these channels (γj, main = 35 pS) and to the low gmin/gmax ratio for these channels. In addition, note that at these low voltages, open probability of Cx45 channels was low and comparable to that of Cx43 at a Vj of 75 mV.
Figure 12. Figure 12.

State diagram of Cx50 gap junction channels. In this scheme, the channels are envisioned to possess two fully open states (O) and a single closed state (C). For each polarity of Vj, the equilibrium between fully open (O) and subconductance state (Os) is determined by the opening and closing rate constants α and β. Transitions between O and C and Os and C are not appreciably voltage sensitive and are presumably the targets of heptanol, halothane, and other uncoupling lipophiles.
Figure 13. Figure 13.

pH sensitivity of Cx43 is mediated through a docking interaction between different domains of the connexin molecule. A: Under control conditions, the carboxyl terminus hangs freely in the cytoplasm; acidification causes a conformational change in which a domain in CT interacts with a binding site located in the cytoplasmic hinge region to close the channel. B: In experiments in which truncated Cx43, lacking CT, is co‐expressed with a peptide corresponding to CT, acidification causes similar channel closure, which is envisioned to result from the same interaction between the blocking particle and the binding site.

Modified from Calero et al. 34
Figure 14. Figure 14.

Phosphorylation of Cx43 in rat cardiac myocytes and in hCx43 transfected SKHep1 cells. Cx43 is a phosphoprotein; extent of phosphorylation depends on activity of protein kinases and phosphatases. Western blot (WB) shows that Cx43 appears in SDS‐PAGE as a triplet of bands with distinct mobilities (labeled P2, P1 and NP in cardiocytes; in hCx43‐transfectants a less mobile band appears that is labeled HP). In autoradiograms (P), only the upper forms are identified, indicating that NP is the dephosphorylated form. Treatment with the protein kinase inhibitor staurosporine (S) decreases phosphate incorporation, whereas treatment with the phosphatase inhibitor okadaic acid (O.A.) increases the intensity of the radiolabel compared to control (C) cultures.

From Spray et al, 1994, with permission
Figure 15. Figure 15.

Effects of infection of rat neonatal cardiac myocytes with Trypanosoma cruzi on synchronous beating and gap junction distribution. Top: Results of two experiments in which beat rates were recorded in matched cultures of uninfected (left) and T. cruzi‐infected (right) cardiac myocytes. Beat rates were recorded in multiple areas of a microscope field using the brightness over time utility program in Image 1AT. Note constant interval between beats in control cultures and highly variable beat rates in infected cultures. Bottom: Redistribution of Cx43 immunoreactivity in T. cruzi‐infected myocytes (right) compared to controls (left). In contrast to strong staining at appositional membranes in control cultures, infected cells exhibited little or no Cx43 immunoreactivity, whereas adjacent cells showed normal Cx43 expression levels. Small arrows indicate the parasites; large arrows point to junctional membranes.

From Campos de Carvalho et al. 35
Figure 16. Figure 16.

Representative ECG recordings from wild‐type, connexin40‐null homozygous (Cx40−/−) and connexin43 heterozygous (Cx43+/−) mice. A: In Cx40‐null hearts atrioventricular and intraventricular conductions are slower, with characteristic longer PR and QRS intervals; partial conduction blockage through His‐Purkinje system leads to uncoordinated ventricular activation with a high incidence of split QRS complex and rSR = morpholog 227. B. Types of arrhythmias in hearts of Cx40−/− mice: (1) sinus arrhythmia; (2) atrial ectopia (third P wave of the tracing); (3) sinus arrhythmia or sino‐atrial block; (4) total AV block; (5) total AV block with ventricular ectopic beat; (6) intra‐atrial re‐entrant tachycardia. C,D: Delayed intraventricular conduction and prolongued QRS interval are observed in Cx43+/− hearts, but other ECG parameters are similar to those recorded from wild‐type mice.

From Kirchhoff et al., 1998, with permission. From Thomas et al., with permission 268


Figure 1.

Ultrastructural features of cardiac gap junctions: From thin section (A,B) and freeze‐fracture (C) electron microscopy to negatively stained isolated junctional membranes (D) and projection density maps (E, F) of gap junctions. A: Transmission electron micrographs of canine myocardium showing the distribution of gap junctions at the intercalated disk. Top panel: The sarcomeric Z‐line (Z) and the junctions within plicate (P, open arrow) and interplicate segments (solid arrow) are evident in this longitudinal section of the myocyte showing typical undulating geometry. Bottom panel: Undulations of apposed junctional membranes are also observed in a transverse section that emphasizes the long dimension of an interplicate gap junction. B: Higher power electron micrograph of gap junction between rat ventricular myocytes showing the characteristic seven‐layered structure and the conspicuous fuzzy coating at both cytoplasmic surfaces. Fixed by vascular perfusion with osmium tetroxide and stained with uranyl acetate and lead citrate (magnification 156 × 103). C: Electron micrograph of replica of freeze‐fractured gap junction between rat ventricular myocytes. Fixed by vascular perfusion with glutaraldehyde and unidirectionally shadowed with platinum‐carbon. The particulate P‐face and the pitted E‐face of the junction are seen on the top and bottom sides of the picture, respectively (magnification 134 × 103). D: In an en face view of junctional membranes isolated from rat ventricle, the hexagonal structure of the connexons are outlined by phosphotungstate deposition around and within the core of the intercellular channels (magnification 241 × 103). E and F: Projection density maps of rat cardiac gap junction obtained at 1.5 nm resolution (E), showing individual hexameric connexons, and at 0.7 nm resolution (F), showing symmetrical circular densities that are interpreted as helices lining the channels, α helices that are most exposed to lipids (arrow) and two continuous dense bands that presumably represent the other two transmembrane α‐helices. Spacing between grid bars is 4 nm.

From Manjunath et al. with permission 153. From Page and Manjunath with permission 188. From Page and Manjunath with permission from reference 188). From Luke and Saffitz, 150, with permission. From Yeager and Nicholson 307 with permission


Figure 2.

Gap junction channels (A) are formed of hemichannels or connexons composed of connexin proteins (B) encoded by connexin genes (C). A: Schematic drawing of gap junction structure deduced from the classical study applying X‐ray diffraction to gap junctions isolated from mouse liver 152. Two connexons dock across extracellular space to form the complete gap junction channel. B: The connexin protein and its membrane topology: the two extracellular loops (C1 and C2), the four transmembrane domains (M1, M2, M3, and M4), the intracellular loop (CL, short in group I or α subfamily and long in group II or β connexin subfamily), and the cytoplasmic amino‐ and carboxyl‐terminal domains (NT and CT). C, top: Connexin gene (exons E1 and E2, intron IVS). C, bottom: Connexin transcript. Transmembrane domains of encoded protein indicated by dark bars.



Figure 3.

Schematic diagram illustrating general pattern of distribution and relative abundance of connexin types expressed in different regions of the mammalian heart and vessel wall.



Figure 4.

Pattern of connexin 43 (Cx43) and desmin distribution during the developmental differentiation of mouse ventricle myocytes as viewed by double immunofluorescence. A: Cross‐sections of newborn mouse ventricular wall showing desmin striations (identifying Z‐lines of myofibrils) and the homogenous distribution of Cx43 between the myocytes. B: Longitudinal sections of two‐week‐old mouse ventricular wall showing the intercalated disks, which are strongly immunoreactive to anti‐desmin antibodies (white arrows) and the initiation of polarized Cx43 expression that progressively becomes restricted to the opposite ends of the myocytes (intercalated disks, white arrows) and to the adjacent lateral regions. C: Longitudinal sections of three‐week‐old mouse ventricular wall showing the even more pronounced polarization of Cx43 expression at the intercalated disks (white arrows) that was first evident at two weeks postpartum. D: Longitudinal section of adult mouse ventricular wall showing that Cx43 expression is now confined to the intercalated disks. This pattern of expression is observed at the conclusion of myocyte differentiation and characterizes myocytes in adult ventricular tissue (bars = 50 μm).

From Fromaget et al. 81 with permission


Figure 5.

Expression patterns of Cx43 (top panels), Cx45 (middle panels), and Cx40 (bottom panels) in the crista terminalis (left panels) and left ventricular muscle (right panels) viewed by immunofluorescence. In the crista terminalis, the distribution of immunoreactivity for the three connexins follows a regular and simple pattern, consistent with the localization of the intercalated disks at the true ends of the atrial myocytes. In the ventricle, the pattern is more complex with side‐to‐side as well as end‐to‐end staining, consistent with the more extensive intercellular junctions that occur between ventricular myocytes.

From Saffitz et al. 219


Figure 6.

Effect of gap junctions on longitudinal (left panels) and transverse propagation (right panels) in a 2D cellular network model. A: Spatial distribution of the depolarization (Vm) for longitudinal (left) and transverse (right) conduction. Bold lines represent changes of Vm within cells; dashed lines represent the step changes in Vm at the gap junctions. Note that time scale on the right is longer, so that signal is more rapidly attenuated (and discrete Vm drops at borders more profound) for transverse conduction. B: Time course of activation within a network of five myocytes (labeled a–e) in the 2D model, arranged longitudinally (left) or transversely (right). C: Excitation isochrones (separated by 4 μsec on the left and 3 μsec on the right) along the longitudinal (left) and transverse (right) axes of the myocytes. Direction of propagation is indicated by arrows.

From Spach and Heidlage, 235


Figure 7.

Regulation of gap junction expression and degradation. A: Diagram of the life cycle of cardiac gap junctions. 1. MRNA is transcribed in the nucleus and translocated to the cytoplasm; 2. Protein is translated and inserted into the Endoplasmic reticulum. Mis‐translated or mis‐folded protein is proteolyzed by the Proteasome . Along the way from ER to Golgi , connexons are formed by connexin oligomerization. The connexons are then transported to the cell surface where they meet and dock and with connexons of adjacent cells to form gap junction channels. Removal of gap junctions is through both proteasomal and lysosomal pathways . B: Transcriptional activity of human connexin43‐luciferase chimeric plasmids transfected into rat cardiac myocytes in vitro and adult rat ventricle myocytes in vivo. On the right, diagrams of the reporter gene constructs with nested deletions from the human Cx43 gene (−2400 to −50 base pairs, relative to transcription initiation). On the left, plot of relative luciferase activity generated by each construct, showing that the presence of at least 175 base pairs of 5′‐flanking sequence is required for measurable transcription. Differences in transcription in in vitro and in vivo experiments was only seen with the 2400 base pair construct. In vivo this construct was 170‐fold more active than the −50Cx43Lux plasmid, while in vitro it was only 30‐fold more active. Each data point represents the mean ± S. E. from three to five different animals. Results in vivo are compared to myocytes in vitro by arbitrarily setting the −250Cx43Lux construct value to 1 for both systems.

Modified from Laing et al. 133. Modified from De Leon et al. 153, with permission


Figure 8.

Model for slow intercellular calcium wave propagation proposed by Sanderson and colleagues 221. Mechanical stimulation of a single cell in culture can induce the activation of phospholipase C (PLC) and synthesis of inositol trisphosphate (IP3), thereby activating IP3 receptors (IP3R) to release calcium from intracellular stores. The diffusion of IP3 to the neighboring cells, passing through gap junction channels, triggers the propagation of calcium waves from cell to cell. An extracellular pathway can also operate in parallel with the intercellular pathway. In this case, an extracellular messenger released from the stimulated cell diffuses from cell to cell and communicates the signal through activation of membrane receptors. In most cells that exhibit this mechanism, ATP has proven to be the extracellular messenger mediating the propagation of the calcium waves through activation of purinoceptors.



Figure 9.

Triggered propagated contraction (TPC) in rat trabeculae. The constant interval between the peak of sarcomere shortening (vertical dotted lines) recorded simultaneously at five different points (300 μm apart) along the trabeculae (length 2.9 mm) during a TPC indicates that the contraction propagates with a constant velocity (1.4 mm/sec) along the preparation. SL = sarcomere length; F = force of contraction.

From ter Keurs and Zhang, 267, with permission


Figure 10.

Dependence of junctional conductance of Cx40, Cx43, and Cx45 gap junction channels on transjunctional voltage (Vj). A: Recordings of junctional current (Ij, lower traces) measured in one cell of a pair expressing each connexin individually in response to 8–15 sec long pulses from 0 to ± 80 mV (in 20 mV increments) that were applied to the other cell. Junctional currents were maximal at the beginning of the pulses and declined to steady‐state values in a time‐ and voltage‐dependent manner. B: Relationship between Vj and steady‐state junctional conductance of Cx40, Cx43, and Cx45 gap junction channels (solid lines) and of Cx37 and Cx50 (dotted lines). The lines are a fit of the normalized steady‐state junctional conductance (Gj, the ratio of the steady‐state gj to maximal gj)‐Vj relationship to a two state Boltzmann equation. The Boltzmann parameters for channels formed by each connexin type are listed in Table 2.



Figure 11.

Unitary conductances of gap junction channels formed by Cx40 (A), Cx43 (B), and Cx45 (C) measured with pipettes containing 130 mM CsCl. A: Top. Junctional currents measured in one cell of a Cx40‐transfected N2A cell pair in response to 16 sec voltage step to 30 mV from a holding potential of 0 mV that was applied to the other cell. Single Cx40 channels were maximally open (O) from the baseline level (C) immediately upon application of a voltage pulse. The amplitude of the unitary current measured from all points amplitude histogram was 5.8 pA, corresponding to a single‐channel conductance of 193 pS. A: Bottom. Single‐channel current voltage (Ij‐Vi) relationships of the junctional current constructed from responses of Cx40‐transfected N2A cells to a series of ramps from −100 to +100 mV. The unitary conductance of the main state (γj, main) and the substate (γj, sub), measured as the slopes of the current‐voltage relationships (solid lines), were 170 pS and 40 pS, respectively. The ratio of γj, sub and γj, main for Cx40 channels is similar to the gmin/gmax value obtained from macroscopic recordings. B, C: Single‐channel currents from Cx43‐ and Cx45‐transfected cell pairs at voltages close to the respective Vi values obtained from macroscopic recordings. B: Single‐channel current through Cx43 gap junction channels predominantly exhibits transitions between a subconductance state (S) and the open state (O) at a Vj of 75 mV. Transitions to the baseline level (C) were rare; only one such transition was observed during the 40‐second pulse. Unitary conductances of the fully open state and the subconductance state were 80 pS and 26 pS, respectively. C: transitions of single‐channel current from a Cx45‐transfected cell pair at a Vj of 30 mV to the subconductance state is not clearly detected due to the small unitary conductance of these channels (γj, main = 35 pS) and to the low gmin/gmax ratio for these channels. In addition, note that at these low voltages, open probability of Cx45 channels was low and comparable to that of Cx43 at a Vj of 75 mV.



Figure 12.

State diagram of Cx50 gap junction channels. In this scheme, the channels are envisioned to possess two fully open states (O) and a single closed state (C). For each polarity of Vj, the equilibrium between fully open (O) and subconductance state (Os) is determined by the opening and closing rate constants α and β. Transitions between O and C and Os and C are not appreciably voltage sensitive and are presumably the targets of heptanol, halothane, and other uncoupling lipophiles.



Figure 13.

pH sensitivity of Cx43 is mediated through a docking interaction between different domains of the connexin molecule. A: Under control conditions, the carboxyl terminus hangs freely in the cytoplasm; acidification causes a conformational change in which a domain in CT interacts with a binding site located in the cytoplasmic hinge region to close the channel. B: In experiments in which truncated Cx43, lacking CT, is co‐expressed with a peptide corresponding to CT, acidification causes similar channel closure, which is envisioned to result from the same interaction between the blocking particle and the binding site.

Modified from Calero et al. 34


Figure 14.

Phosphorylation of Cx43 in rat cardiac myocytes and in hCx43 transfected SKHep1 cells. Cx43 is a phosphoprotein; extent of phosphorylation depends on activity of protein kinases and phosphatases. Western blot (WB) shows that Cx43 appears in SDS‐PAGE as a triplet of bands with distinct mobilities (labeled P2, P1 and NP in cardiocytes; in hCx43‐transfectants a less mobile band appears that is labeled HP). In autoradiograms (P), only the upper forms are identified, indicating that NP is the dephosphorylated form. Treatment with the protein kinase inhibitor staurosporine (S) decreases phosphate incorporation, whereas treatment with the phosphatase inhibitor okadaic acid (O.A.) increases the intensity of the radiolabel compared to control (C) cultures.

From Spray et al, 1994, with permission


Figure 15.

Effects of infection of rat neonatal cardiac myocytes with Trypanosoma cruzi on synchronous beating and gap junction distribution. Top: Results of two experiments in which beat rates were recorded in matched cultures of uninfected (left) and T. cruzi‐infected (right) cardiac myocytes. Beat rates were recorded in multiple areas of a microscope field using the brightness over time utility program in Image 1AT. Note constant interval between beats in control cultures and highly variable beat rates in infected cultures. Bottom: Redistribution of Cx43 immunoreactivity in T. cruzi‐infected myocytes (right) compared to controls (left). In contrast to strong staining at appositional membranes in control cultures, infected cells exhibited little or no Cx43 immunoreactivity, whereas adjacent cells showed normal Cx43 expression levels. Small arrows indicate the parasites; large arrows point to junctional membranes.

From Campos de Carvalho et al. 35


Figure 16.

Representative ECG recordings from wild‐type, connexin40‐null homozygous (Cx40−/−) and connexin43 heterozygous (Cx43+/−) mice. A: In Cx40‐null hearts atrioventricular and intraventricular conductions are slower, with characteristic longer PR and QRS intervals; partial conduction blockage through His‐Purkinje system leads to uncoordinated ventricular activation with a high incidence of split QRS complex and rSR = morpholog 227. B. Types of arrhythmias in hearts of Cx40−/− mice: (1) sinus arrhythmia; (2) atrial ectopia (third P wave of the tracing); (3) sinus arrhythmia or sino‐atrial block; (4) total AV block; (5) total AV block with ventricular ectopic beat; (6) intra‐atrial re‐entrant tachycardia. C,D: Delayed intraventricular conduction and prolongued QRS interval are observed in Cx43+/− hearts, but other ECG parameters are similar to those recorded from wild‐type mice.

From Kirchhoff et al., 1998, with permission. From Thomas et al., with permission 268
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Article Title: Gap Junctions in the Cardiovascular System
 

How to Cite

David C. Spray, Sylvia O. Suadicani, Miduturu Srinivas, David E. Gutstein, Glenn I. Fishman. Gap Junctions in the Cardiovascular System. Compr Physiol 2011, Supplement 6: Handbook of Physiology, The Cardiovascular System, The Heart: 169-212. First published in print 2002. doi: 10.1002/cphy.cp020104