Comprehensive Physiology Wiley Online Library

Gap Junctions in the Cardiovascular System

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 . From Page and Manjunath with permission . From Page and Manjunath with permission from reference ). From Luke and Saffitz, , with permission. From Yeager and Nicholson 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 . 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. 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.
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,
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. . Modified from De Leon et al. , with permission
Figure 8. Figure 8.

Model for slow intercellular calcium wave propagation proposed by Sanderson and colleagues . 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, , 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 .

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.
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.
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 . 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


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 . From Page and Manjunath with permission . From Page and Manjunath with permission from reference ). From Luke and Saffitz, , with permission. From Yeager and Nicholson 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 . 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. 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.


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,


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. . Modified from De Leon et al. , with permission


Figure 8.

Model for slow intercellular calcium wave propagation proposed by Sanderson and colleagues . 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, , 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 .



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.


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.


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 . 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
References
 1. Ai, Z., A. Fischer, D. C. Spray, A. M. Brown and G. I. Fishman. Wnt‐1 regulation of connexin43 in cardiac myocytes. J. Clin. Invest. 105: 161–171, 2000.
 2. Anumonwo, J. M., H. Z. Wang, E. Trabka‐Janik, B. Dunham, R. D. Veenstra, M. Delmar and J. Jalife. Gap junctional channels in adult mammalian sinus nodal cells. Immunolocalization and electrophysiology. Circ. Res. 71: 229–239, 1992.
 3. Aonuma, S., Y. Kohama, K. Akai, et al. Studies on heart XIX: isolation of an atrial peptide that improves the rhythmicity of cultured myocardial cell clusters. Chem. Pharm. Bull 28: 332–229, 1980.
 4. Aonuma, S., Y. Kohana, T. Makino, et al. Studies on heart XXII: inhibitory effect of an atrial peptide on several drug induced arrhythmias in vivo. Yakugaku Zasshi, 103: 662–666, 1983.
 5. Bai, S., D. C. Spray and R. Burk. Characterization of rat connexin32 gene regulatory elements. In Gap Junctions (J. Hall, G. Zampighi and R. E. Davis, Eds), Elsevier. 1993; 291–297.
 6. Banach, K., R. Weingart. Connexin43 gap junctions exhibit asymmetrical gating properties. Pflugers Arch. Eur. J. Physiol. 431: 775–785, 1996.
 7. Barr, L., M. M. Dewey and W. Berger. Propagation of action potentials and the structure of the nexus in cardiac muscle. J. Gen. Physiol. 48: 797–823, 1965.
 8. Barrio, L. C., J. Capel, J. A. Jarillo, C. Castro, and A. Revilla. Species‐specific voltage‐gating properties of connexin‐45 junctions expressed in Xenopus oocytes. Biophys. J. 73: 757–769, 1997.
 9. Barrio, L. C., T. Suchyna, T. Bargiello, L. X. Xu, R. S. Roginski, M. V. Bennett and B. J. Nicholson. Gap junctions formed by connexins 26 and 32 alone and in combination are differently affected by applied voltage. Proc. Natl. Acad. Sci. U.S.A. 88: 8410–8414, 1991.
 10. Bastiaanse, E. M., H. J. Jongsma, A. van dr Laarse, and B. R. Takens‐Kwak. Heptanol‐induced decrease in cardiac gap junctional conductance is mediated by a decrease in the fluidity of membranous cholesterol‐rich domains. J. Membr. Biol. 136: 135–145, 1993.
 11. Bastide, B., L. Neyses, D. Ganten, M. Paul, K. Willecke and O. Traub. Gap junction protein connexin40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions. Circ. Res. 73: 1138–1149, 1993.
 12. Beardslee, M. A., J. G. Laing, E. C. Beyer and J. E. Saffitz. Rapid turnover of connexin43 in the adult rat heart. Circ Res, 83: 629–635, 1998.
 13. Beblo, D. A., H.‐Z. Wang, E. C. Beyer, E. Westphale, and R. D. Veenstra. Unique conductance, gating and selective permeability properties of gap junction channels formed by connexin40. Circ. Res. 77: 813–822, 1995.
 14. Beblo, D. A. and R. D. Veenstra. Monovalent cation permeation through the connexin40 gap junction channel. Cs, Rb, K, Na, Li, TEA, TMA, TBA, and effects of anions Br, Cl, F, acetate, aspartate, glutamate, and NO3. J. Gen. Physiol. 109: 509–522, 1997.
 15. Benedetti, E. L., and P. Emmelot. Electron microscopic observations on negatively stained plasma membranes isolated from rat liver. J. Cell. Biol. 26: 299–305, 1965.
 16. Bennett, M. V. L., L. C. Barrio, T. A. Bargiello, D. C. Spray, E. Hertzberg and J. C. Saez. Gap junctions:new tools, new answers, new questions. Neuron 6: 305–320, 1991.
 17. Bennett, M. V., J. C. Saez, and D. C. Spray. Multiplicity of controls of gap junctional communication. P.R. Health Sci J. 7: 126, 1988.
 18. Bennett, M. V. L., X. Zheng and M. L. Sogin. The connexins and their family tree. In: Molecular Evolution of Physiological Processes, edited by D. Fambrough, 47th Annual Symposium of the Society of General Physiologists, vol. 49, 1994: 223–233.
 19. Beyer, E. C., D. L. Paul, and D. A. Goodenough. Connexin43: a protein from rat heart homologous to the gap junction protein from liver. J. Cell. Biol. 105: 2621–2629, 1987.
 20. Beyer, E. C., K. E. Reed, E. M. Westphale, H. L. Kanter, and D. M. Larson. Molecular cloning and expression of rat connexin40, a gap junction protein expressed in vascular smooth muscle. J. Memb. Biol. 127; 69–76, 1992.
 21. Blankesteijin, W. M., Y. P. Essers‐Janssen, M. M. Ulrich and J. F. Smits. Increased expression of a homologue of Drosophila tissue polarity gene “frizzled” in left ventricular hypertrophy in the rat, as identified by subtractive hybridization. J. Mol. Cell. Cardiol. 29: 1187–1191, 1996.
 22. Blankesteijin, W. M., Y. P. Essers‐Janssen, M. J. Verluyten, M. J. Daemen and J. F. Smits. A homologue of Drosophila tissue polarity gene frizzled is expressed in migrating myofibroblasts in the infarcted rat heart. Nat. Med. 3: 541–544, 1997.
 23. Boitano, S., E. R. Dirksen, and W. H. Evans. Sequence‐specific antibodies to connexins block intercellular calcium signalig through gap junctions. Cell Calcium 23: 1–9, 1998.
 24. Brink, P. R., S. V. Ramanan, and G. J. Christ. Human conexin43 gap junction channel gating: evidence for mode shifts and/or heterogeneity. Am. J. Physiol. 271: C321–331, 1996.
 25. Britz‐Cunningham, S. H., M. M. Shah, C. W. Zuppan and W. H. Fletcher. Mutations of the connexin43 gap‐junction gene in patients with heart malformations and defects of laterality. N. Engl. J. Med. 332: 1323–1329, 1995.
 26. Bruzzone, R., J.‐A. Haefflinger, R. L. Gimlich, and D. L. Paul. Connexin40, a component of gap junctions in vascular endothelium, is restricted in its ability to interact with other connexins. Mol. Cell. Biol. 4: 7–20, 1993.
 27. Bukauskas, F. F., C. Elfgang, K. Willecke and R. Weingart. Biophysical properties of gap junction channels formed by mouse connexin40 in induced pairs of transfected human HeLa cells. Biophys. J. 68: 2289–2298, 1995.
 28. Bukauskas, F. F. and C. Peracchia. Two distinct gating mechanisms in gap junction channels: CO2‐sensitive and voltagesensitive. Biophys. J. 72: 2137–2142, 1997.
 29. Bukauskas, F. F. and R. Weingart. Multiple conductance states of newly formed single gap junction channels between insect cells Pflugers Arch. 423: 152–154, 1993.
 30. Bukauskas, F. F. and R. Weingart. Voltage‐dependent gating of single gap junction channels in an insect cell line. Biophys. J. 67: 613–625, 1994.
 31. Burt, J. M. Uncoupling of cardiac cells by doxyl stearic acid specificity and mechanism of action. Am. J. Physiol. 256: C913–C924, 1989.
 32. Burt, J. M. and D. C. Spray. Single channel events and gating behavior of the cardiac gap junction channel. Proc. Natl. Acad. Sci, U.S.A., 85: 3431–3434, 1988.
 33. Cabo, C., A. M. Pertsov, W. T. Baxter, J. M. Davidenko, R. A. Gray and J. Jalife. Wave‐front curvature as a cause of slow conduction and block in isolated cardiac muscle. Circ. Res. 75: 1014–1028, 1994.
 34. Calero, G., M. Kanemitsu, S. M. Taffet, A. F. Lau, and M. Delmar. A 17mer peptide interferes with acidification‐induced uncoupling of connexin43. Circ. Res. 18: 929–935, 1998.
 35. Campos de Carvalho, A. C., H. B. Tanowitz, M. Wittner, R. Dermietzel, C. Roy, E. L. Hertzberg, and D. C. Spray. Gap junction distribution is altered between cardiac myocytes infected with Trypanosoma cruzi Circ. Res. 70: 733, 1992.
 36. Chaytor, A. T., W. H. Evans, and T. M. Griffith. Peptides homologous to extracellular loop motifs of connexin43 reversibly abolish rhythmic contractile activity in rabbit arteries. J. Physiol. 15: 99–110, 1997.
 37. Chen, Y.‐H. and R. L. DeHaan. Asymmetric voltage dependence of embryonic cardiac gap junction channels. Am. J. Physiol. 270: C276–C285, 1996.
 38. Chen, Z. Q., D. Lefebvre, X. H. Bai, A. Reaume, J. Rossant, and S. J. Lye. Identification of two regulatory elements within the promoter region of the mouse connexin 43 gene. J. Biol. Chem. 270: 3863–3868, 1995.
 39. Christ, G. J., D. C. Spray, M. el‐Sabban, L. K. Moore, and P. R. Brink. Gap junctions in vascular tissues. Evaluating the role of intercellular communication in the modulation of vasomotor tone. Circ. Res. 79: 631–646, 1996.
 40. Clerc, L. Directional differences of impulse spread in trabecular muscle from mammalian heart. J. Phyisol. (Lond). 125: 221–224, 1954.
 41. Cole, W. C. and R. E. Garfield. Evidence for physiological regulation of myometrial gap junction permeability. Am. J. Physiol. 251: C411–C420, 1986.
 42. Condorelli, D. F., R. Parenti, F. Spinella, A. T. Salinaro, N. Belluardo, V. Cardile and F. Cicirata. Cloning of a new gap junction gene (Cx36) highly expressed in mammalian brain neurons. Eur. J. Neurosci. 10: 1202–1208, 1998.
 43. Coppen, S. R., E. Dupont, S. Rothery, and N. J. Severs. Connexin45 expression is preferentially associated with the ventricular conduction system in mouse and rat heart. Circ. Res. 82: 232–243, 1998.
 44. Coppen, S. R., I. Kodama, M. R. Boyett, H. Dobrzynski, Y. Takagishi, H. Honjo, H. I. Yeh, and N. J. Severs. Connexin45, a major connexin of the rabbit sinoatrial node, is co‐expressed with connexin43 in a restricted zone at the nodal‐crista terminalis border. J. Histochem. Cytochem. 47: 907–918, 1999.
 45. Coppen, S. R., N. J. Severs and R. G. Gourdie. Connexin45(alpha 6) expression delineates an extended conduction system in the embryonic and mature rodent heart. Dev. Genet. 24: 82–90, 1999.
 46. Cowan, D. B., S. J. Lye and B. L. Langille. Regulation of vascular connexin43 gene expression by mechanical loads. Circ. Res. 82: 786–793, 1998.
 47. Curtin, K. D., Z. Zhang and R. J. Wyman. Drosophila has several genes for gap junction proteins. Gene 232: 191–201, 1999.
 48. Daniels, M. C., T. Kieser, and H. E. ter Keurs. Triggered propagated contractions in human atrial trabeculae. Cardiovasc. Res. 27: 1831–1835, 1993.
 49. Daniels, M. C. G. and H. E. D. ter Keurs. Spontaneous contractions in rat cardiac trabeculae: trigger mechanism and propagation velocity. J. Gen. Physiol. 95: 1123–1137, 1990.
 50. Davidson, J. S. and I. M. Baumgarten. Glycyrrhetinic acid derivatives: a novel class of inhibitors of gap‐junctional intercellular communication. Structure‐activity relationships. J. Pharm Acol. Exp. Ther. 246: 1104–1107, 1988.
 51. Davis, L. M., M. E. Rodefeld, K. Green, E. C. Beyer, and J. E. Saffitz. Gap junction protein phenotypes of the human heart and conduction system. J. Cardiovasc. Electrophysiol. 6: 813–822, 1995.
 52. De Bakker, J. M. T., F. J. L. Van Capelle, M. J. Janse, et al. Slow conduction in the infarcted human heart Azig zag course of activation. Circulation 88: 915–926, 1993.
 53. De Leon, J. R., P. M. Buttrick, and G. I. Fishman. Functional analysis of the connexin43 gene promoter in vivo and in vitro. J. Mol. Cell. Cardiol. 26: 379–389, 1994.
 54. Deleze, J. The recovery of resting potential and input resistance in sheep heart injured by knife or laser. J. Physiol. (Lond.) 208: 548–562, 1970.
 55. Delorme, B., E. Dahl, T. Jarry‐Guichard, I. Marics, J. P. Briand, K. Willecke, D. Gros and M. Theveniau‐Ruissy. Developmental regulation of connexin40 gene expression in mouse heart correlates with the differentiation of the conduction system. Dev. Dyn. 204: 358–371, 1995.
 56. DeMaziere, A. M. G. L. and D. W. Scheuermann. Morphological analysis of gap‐junctional area in parenchymal cells of the rat liver after administration of dibutyryl cAMP and aminophylline. Cell Tissue Res. 252: 611–618, 1988.
 57. De Mello, W. C. Effect of intracellular injection of cAMP on the electrical coupling of mammalian cardiac cells. Biochem. Biphys. Res. Commun. 119: 1001–1107, 1984.
 58. De Mello, W. C. The influence of pH on the healing‐over of mammalian cardiac muscle. J. Physiol. 339: 299–307, 1983.
 59. De Mello, W. C., G. E. Motta, and M. Chapeau. A study on the healing‐over of myocardial cells of toads. Circ. Res. 24: 475–487, 1969.
 60. Dewey, M. M. and L. Barr. Intercellular connection between smooth muscle cells: the nexus. Science 137: 670, 1962.
 61. Dhein, S. and T. Tudyka. Therapeutic potential of antiarrhythmic peptides: cellular coupling as a new antiarrhythmic target. Drugs 49: 851–855, 1995.
 62. Dhein, S., T. Tudyka, M. Schott, W. Gottwald, D. Piecha, A. Muller, and W. Klaus. Enhancement of cellular coupling as a possible new antiarrythmic mechanism. Naunyn Schmiedeberg's Arch. Pharmacol. 351, [Suppl]: R106. 1995.
 63. Diez, J. A., S. Ahmad, and W. H. Evans: Biogenesis of liver gap junctions. In: Gap Junctions, edited by R. Werner. Amsterdam: IOS Press, 1998: 130–134.
 64. Dunlap, K., K. Takeda and P. Brehm. Activation of calciumdependent photoprotein by chemical signalling through gap junctions. Nature 325: 60–62, 1987.
 65. Eckert, R., A. Dunina‐Barkovskaya and D. F. Hulser. Biophysical characterization of gap‐junction channels in HeLa cells. Pflugers Arch 424: 335–342, 1993.
 66. Eghbali, B., J. A. Kessler and D. C. Spray. Expression of gap junction channels in a communication incompetent cell line after transfection with connexin32 cDNA. Proc. Natl. Acad. Sci. U.S.A. 87; 1328–1331, 1990.
 67. Ek, J. F., M. Delmar, R. Perzova, and S. M. Taffet. Role of histidine 95 on pH gating of the cardiac gap junction protein connexin43. Circ. Res. 74: 1058–1064, 1994.
 68. Ek‐Vitorin, J. F., G. Calero, G. E. Morley, W. Coombs, S. M. Taffet, and M. Delmar. pH regulation of connexin43: molecular analysis of the gating particle. Biophys. J. 7: 1273–1284, 1996.
 69. Elenes, S., M. Rubart and A. P. Moreno. Junctional communication between isolated pairs of canine atrial cells is mediated by homogeneous and heterogeneous gap junction channels. J. Cardiovasc. Electrophysiol. 10: 990–1004, 1999.
 70. Elfgang, C., R. Eckert, H. Lichtembderg‐Fiate, A. Butterweek, O. Traub, R. A. Klein, D. F. Huber and E. K. Willecke. Specific permeability and selective formation of gap junction channels in connexin‐transfected HeLa cells. J. Cell. Biol. 129: 805–817, 1995.
 71. Engelmann, T. W. Ueber die Leitung der Erregung im Herzmuskel. Pflugers Arch. Physiol. 11: 465–480, 1877.
 72. Epstein, M. L. and N. B. Gilula. A study of communication specificity between cells in culture. J. Cell. Biol. 75: 769–787, 1977.
 73. Ewart, J. L., M. F. Cohen, R. A. Meyer, G. Y. Huang, A. Wessels, R. G. Gourdie, A. J. Chin, S. M. Park, B. O. Lazatin, S. Villabon and C. W. Lo. Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene. Development 124: 1281–1292, 1997.
 74. Falk, M. M., N. M. Kumar, and N. B. Gilula. Membrane insertion of gap junction connexins: polytopic channel forming membrane proteins. J. Cell. Biol. 127: 343–355, 1994.
 75. Falk, M. M., and N. B. Gilula. Connexin membrane protein biosynthesis is influenced by polypeptide positioning within the translocon and signal peptidase access. J. Biol. Chem. 273: 7856–7864, 1998.
 76. Fallon, R. F. and D. A. Goodenough. Five‐hour half‐life of mouse liver gap‐junction protein. J. Cell Biol. 90: 521–526, 1981.
 77. Firek, L., and R. Weingart. Modification of gap junction conductance by divalent cations and protons in neonatal rat heart cells. J. Mol. Cell. Cardiol. 27: 1633–1643, 1995.
 78. Fishman, G. I., A. P. Moreno, D. C. Spray, and L. A. Leinwand. Functional analysis of human cardiac gap junction channel mutants. Proc. Natl. Acad. Sci U.S.A. 88: 3525–3529, 1991.
 79. Fishman, G., D. C. Spray, and L. A. Leinwand. Molecular characterization and functional expression of the human cardiac gap junction channel. J. Cell Biol. 111: 589–598, 1990.
 80. Fluri, G. S., A. Rudisuli, M. Willi, S. Rohr and R. Weingart. Effects of arachidonic acid on the gap junctions of neonatal rat heart cells. Pflugers Arch. Eur. J. Physiol. 417: 149–156, 1990.
 81. Fromaget, C., A. El Aoumari, and D. Gros. Distribution pattern of connexin 43, a gap junction protein, during the differentiation of mouse heart myocytes. Differentiation 51: 9–20, 1992.
 82. Gabriels, J. E., and D. L. Paul: Connexin43 is highly localized to sites of disturbed flow in rat aortic endothelium while connexin37 and connexin40 are more uniformly distributed. Circ. Res. 83: 636–643, 1998.
 83. Garfield, R. E., S. M. Sims, M. S. Kannan, and E. E. Daniel. Possible role of gap junctions in activation of myometrium during parturition. Am. J. Physiol. 235: C168–C179, 1978.
 84. Geimonen, E., O. Etchelsu, W. Jiang, et al. An AP‐1 site in the human connexin43 promoter sequence mediates induction of transcription in uterine somooth muscle cells following treatment with phorbol ester. Biol. Chem. 271: 23667–23674, 1996.
 85. Giepmans, B. N. G., W. H. Moolenaar. The gap junction protein connexin43 interactions with the second PDZ domain of the zona occludens‐1 protein. Curr. Biol. 8: 931–934, 1998.
 86. Goldberg, G. S., K. D. Martyn, and A. F. Lau. A connexin 43 antisense vector reduces the ability of normal cells to inhibit the foci formation of transformed cells. Mol. Carcinog. 11: 106–114, 1994.
 87. Gros, D., and C. E. Challice. Early development of gap junctions between the mouse embryonic myocardial cells. A freeeze‐etching study. Experientia 32: 996–998, 1976.
 88. Gros, D., T. Jarry‐Guichard, L. Ten Velde de Maziere, A., M. J. Van Kempen, J. Davoust, J. P. Briand, A. F. Moorman, and H. J. Jongsma. Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. Circ. Res. 74: 839–851, 1994.
 89. Gourdie, R., C. Green, N. Severs, and R. Thompson: Immuno‐labelling patterns of gap junction connexins in the developing and mature rat heart. Anat. Embyryol. 185: 363–378, 1992.
 90. Granot, I., and N. Dekel. Phosphorylation and expression of connexin‐43 ovarian gap junction protein are regulatd by luteinizing hormone. J. Biol. Chem. 269: 30502–30509, 1994.
 91. Gu, H., J. F. Ek‐Vitorin, S. M. Taffet, and M. Delmar. Coexpression of connexins 40 and 43 enhances the pH sensitivity of gap junctions: a model for synergistic interactions among connexins. Circ. Res. 86: E98–E103, 2000.
 92. Guan, X., B. F. Cravatt, G. R. Ehring, J. E. Hall, D. L. Boger, R. A. Lerner, and N. B. Gilula. The sleep‐inducing lipid oleamide deconvolutes gap junction communication and calcium wave transmission in glial cells. J. Cell Biol. 139: 1785–1792, 1997.
 93. Guerrero, P. A., R. B. Schuessler, L. M. Davis, E. C. Beyer, C. M. Johnson, K. A. Yamada, and J. E. Saffitz. Slow ventricular conduction in mice heterozygous for a connexin43 null mutation. J. Clin. Invest. 15: 1991–1998, 1995.
 94. Haefliger, J. A., E. Casatillo, G. Waeber, J. F. Aubert, P. Nicod, B. Waeber, and P. Meda. Hypertension differentially affects the expression of the gap junction protein connexin43 in cardiac myocytes and aortic smooth muscle cells. Adv. Exp. Med. Biol. 432: 71–82, 1997.
 95. Haefliger, J. A., R. Polikar, G. Schnyder, M. Burdet, E. Sutter, T. Pexieder, P. Nicod, and P. Meda. Connexin37 in normal and pathological development of mouse heart and great arteries. Dev. Dyn. 218: 331–344, 2000.
 96. Harris, A. L., D. C. Spray, and M. V. Bennett. Kinetic properties of a voltage‐dependent junctional conductance. J. Gen. Physiol. 77: 95–117, 1981.
 97. Hassinger, T. D., P. B. Guthrie, P. B. Atkinson, M. V. L. Bennett, and S. B. Kater. An extracellular signaling component in propagation of astrocytic calcium waves. Proc. Natl. Acad. Sci. U.S.A. 93: 13268–13273, 1996.
 98. Haubrich, S., H. J. Schwarz, F. Bukauskas, H. Lichtenberg‐Frate, O. Traub, R. Weingart and K. Willecke. Incompatibility of connexin 40 and 43 hemichannels in gap junctions between mammalian cells is determined by intracellular domains. Mol. Biol. Cell 7: 1995–2006, 1996.
 99. He, D. S., and J. M. Burt. Mechanism and selectivity of the effects of halothane on gap junction channel function. Circ. Res. 86: E104–109, 2000.
 100. He, D. S., J. X. Jiang, S. M. Taffet, and J. M. Burt. Formation of heteromeric gap junction channels by connexins40 and 43 in vascular smooth muscle cells. Proc. Natl. Acad. Sci. U.S.A. 96: 6495–6500, 1999.
 101. Hellmann, P., E. Winterhager, and D. C. Spray. Properties of connexin40 gap junction channels endogenously expressed and exogenously overexpressed in human choriocarcinoma cell lines. Eur. J. Physiol. 432: 501–509, 1996.
 102. Hennemann, H., T. Suchyna, H. Lichtenberg‐Frate, S. Jung‐bluth, E. Dahl, J. Schwartz, B. J. Nicholson, and K. Willecke. Molecular cloning and functional expression of mouse connexin40, a second gap junction gene preferentially expressed in lung. J. Cell Biol. 117: 1299–310, 1992.
 103. Hermans, M. M., P. Kortekaas, H. J. Jongsma, and M. B. Rook. pH sensitivity of the cardiac gap junction proteins, connexin 34 and 43. Pflugers Arch 431 (1): 138–140, 1995.
 104. Hertlein, B., A. Butterweck, S. Haubrich, K. Willecke, and O. Traub: Phosphorylated carboxy terminal serine residues stabilize the mouse gap junction protein connexin45 against degradation. J. Membr. Biol. 162: 247–257, 1998.
 105. Heynkes, R., G. Kozjek, O. Traub, and K. Willecke. Identification of a rat liver cDNA and mRNA coding for the 28 kDa gap junction protein. FEBS Lett. 205: 56–60, 1986.
 106. Hirschi, K. K., B. N. Minnich, L. K. Moore, and J. M. Burt. Oleic acid differentially affects gap junction‐mediated communication in heart and vascular smooth muscle cells. Am. J. Physiol. 265: C1517–1526, 1993.
 107. Hofer, A., and R. Dermietzel. Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes. Glia 24: 141–154, 1998.
 108. Horres, C., M. Lieberman, and J. Purdy. Growth orientation of heart cells on nylon monofilament. J. Membr. Biol. 34: 313–329, 1977.
 109. Hoyt, R. H., M. L. Cohen, and J. E. Saffitz. Distribution and three‐dimensional structure of intercellular junctions in canine myocardium. Circ. Res. 64: 563–574, 1989.
 110. Huttner, I., P. M. Costabella, C. De Chastonay, and G. Gabbiani. Volume, surface, and junctions of rat aortic endothelium during experimental hypertension: a morphometric and freeze fracture study. Lab. Invest. 46: 489–504, 1982.
 111. Jiang, J. X. and D. A. Goodenough. Heteromeric connexons in lens gap junction channels. Proc. Natl. Acad. Sci. USA 93: 1287–1291, 1996.
 112. Johnston, M. F., S. A. Simon, and F. Ramon. Interaction of anaesthetics with electrical synapses. Nature 286: 498–500, 1980.
 113. Jongsma, H. J., M. Masson‐Pevet, and L. Tsjernina. The development of beat‐rate synchronization of rat myocyte pairs in cell culture. Basic Res. Cardiol. 82: 454–464, 1987.
 114. Kanemitsu, M. Y., L. W. Loo, S. Simon, A. F. Lau, and W. Eckhart. Tyrosine phosphorylation of connexin 43 by v‐Src is mediated by SH2 and SH3 domain interactions. J. Biol. Chem. 272: 22824–22831, 1997.
 115. Kaprielian, R. R., M. Gunning, E. Dupont, M. N. Sheppard, S. M. Rothery, R. Underwood, D. J. Pennell, K. Fox, J. Pepper, P. A. Poole‐Wilson, and N. J. Severs. Downregulation of immunodetectable connexin43 and decreased gap junction size in the pathogenesis of chronic hibernation in the human left ventricle. Circulation 97: 651–660, 1998.
 116. Kensler, R. W. and D. A. Goodenough. Isolation of mouse myocardial gap junctions. J. Cell Biol. 86: 755–764, 1980.
 117. Kessler, J. A., D. C. Spray, J. C. Sáez, and M. V. L. Bennett. Determination of synaptic phenotype: insulin and cAMP independently initiate development of electrotonic coupling between cultured sympathetic neurons. Proc. Natl. Acad. Sci. U.S.A. 81: 6235–6239, 1984.
 118. Kijima, Y., A. Saito, T. L. Jetton, M. A. Magnuson, and S. Fleischer. Different intracellular localization of inositol 1,4,5–triphosphate and ryanodine receptors in cardiomyocytes. J. Biol. Chem. 268: 3499–3506, 1993.
 119. Kirchhoff, S., E. Nelles, A. Hagendorff, O. Kruger, O. Truab, and K. Willecke. Reduced cardiac conduction velocity and predisposition to arrhythmias in connexin40‐deficient mice. Curr. Biol. 299–302, 1998.
 120. Kleber, A. G. Consequences of acute ischemia for the electrical and mechanical function of the ventricular myocardium. A brief review. Experientia 46: 1162–1167, 1990.
 121. Kleber, A. G., V. G. Faast, and S. Rohr. Microscopic conduction in cell cultures assessed by high‐resolution optical mappin and computer simulation. In: Discontinuous Conduction in the Heart, edited by P. M. Spooner, R. W. Joyner, and J. Jalife. Armonk, NY: Futura 1997: 241–259.
 122. Kleber, A. G., C. B. Riegger, and M. J. Janse. Electrical uncoupling and increase of extracellular resistance after induction of ischemia in isolated, arterially perfused rabbit papillary muscle. Circ. Res. 61: 271–279, 1987.
 123. Kosaki, K., J. Ando, R. Korenaga, T. Kurokawa, and A. Kamiya. Fluid shear stress increases the production of granulocyte‐macrophage colony‐stimulating factor by endothelial cells via mRNA stabilization. Circ. Res. 82: 794–802, 1998.
 124. Kren, B. T., N. M. Kumar, S. Q. Wang, N. B. Gilula, and C. J. Steer. Differential regulation of multiple gap junction transcripts and proteins during rat liver regeneration. J. Cell. Biol. 123: 707–718, 1993.
 125. Kreutziger, G. O. Freeze‐etching of intercellular junctions of mouse liver. In: Proceedings 26th Annual Meeting Electron Microscopy Society of America, edited by C. J. Arceneaux. Baton Rouge, LA: Claitor's, 1968: 234–235.
 126. Kumar, N. M. and N. B. Gilula. The gap junction communication channel. Cell 84: 381–388, 1996.
 127. Kumar, N. M., D. S. Friend, and N. B. Gilula. Synthesis and assembly of human beta 1 gap junctions in BHK cells by DNA transfection with the human beta 1 cDNA. J. Cell. Sci. 108: 3725–3734, 1995.
 128. Kumar, N. M., and N. B. Gilula. Cloning and characterization of human and rat liver cDNAs coding for a gap juction protein. J. Cell Biol. 103: 767–776, 1986.
 129. Kwak, B. R., J. C. Sáez, R. Wilders, M. Chanson, G. I. Fishman, E. L. Hertzberg, D. C. Spray, and H. J. Jongsma. Effects of cGMP‐dependent phosphorylation on rat and human connexin43 gap junction channels. Eur. J. Physiol. 430: 770–778, 1995.
 130. Kwong, K. F., R. B. Schuessler, K. G. Green, J. G. Laing, E. C. Beyer, J. P. Boineau, and J. E. Saffitz. Differential expression of gap junction proteins in the canine sinus node. Circ. Res. 23: 604–612, 1998.
 131. Laing, J. G., and E. C. Beyer. The gap junction protein connexin43 is degraded via the ubiquitin proteasome pathway. J. Biol. Chem. 270: 26399–26403, 1995.
 132. Laing, J. G., E. M. Westphale, G. L. Engelmann, and E. C. Beyer. Characterization of the gap junction protein, connexin45. J. Membr. Biol. 139: 1–40, 1994.
 133. Laing, J. G., P. N. Tadros, E. M. Westphale, and E. C. Beyer. Degradation of connexin43 gap junctions involves both the proteasome and the lysosome. Exp. Cell. Res. 236: 482–492, 1997.
 134. Laing, J. G., P. N. Tadros, and E. C. Beyer. Cx43 gap junction proteolysis involves both the lysosome and the proteasome. In: Gap Junctions, edited by R. Werner, The Amsterdam IOS Press 1998: 112–116.
 135. Laird, D. W. Turnover and phosphorylation of dynamics of connexin43 gap junction protein in cultured cardiac myocytes. Biochem. J. 273: 67–72, 1991.
 136. Laird, D. W. The life cycle of a connexin: gap junction formation, removal, and degradation. J. Bioenerg. Biomembr. 28: 311–318, 1996.
 137. Lal, R. and M. F. Arnsdorf. Voltage‐dependent gating and single‐channel conductance of adult mammalian atrial gap junctions. Circ. Res. 71: 737–743, 1992.
 138. Larsen, W. J., H. N. Tung, S. A. Murray, C. A. Swenson, and W. Larsen. Evidence for the participation of actin microfilaments and bristle coats in the internalization of gap junction membrane. J. Cell. Biol. 83: 576–587, 1979.
 139. Larson, D. M., M. J. Wrobleski, G. D. Sagar, E. M. Westphale, and E. C. Beyer. Differential regulation of connexin43 and connexin37 in endothelial cells by cell density, growth, and TGF‐beta1. Am. J. Physiol. 272: C405–C415, 1997.
 140. Lau, A. F., W. E. Kurata, M. Y. Kanemmitsu, L. W. Loo, B. J. Warn‐Cramer, W. Eckhart, and P. D. Lampe. Regulation of connexin43 function by activated tyrosine protein kinases. J. Bioenerg. Biomembr. 28: 359–368, 1996.
 141. Lee, P., G. Morley, Q. Huang, A. Fischer, S. Seiler, J. W. Horner, S. Factor, D. Vaidya, J. Jalife, and G. I. Fishman. Conditional lineage ablation to model human diseases. Proc. Natl. Acad. Sci. U.S.A. 95: 11371–11376, 1998.
 142. Lee, S. W., C. Tomasetto, D. Paul, K. Keyomarsi, and R. Sager. Transcriptional downregulation of gap‐junction proteins blocks junctional communication in human mammary tumor cells. J. Cell Biol. 118: 1213–1221, 1992.
 143. Lerner, D. L., K. A. Yamada, R. B. Schuessler, and J. E. Saffitz. Accelerated onset and increased incidence of ventricular arrhythmias induced by ischemia in Cx43‐deficient mice. Circulation 101: 547–552, 2000.
 144. Lieberman, M., A. E. Roggeveen, J. E. Purdy, and E. A. Johnsson. Synthetic strands of cardiac muscle: growth and physiological implications. Science 175: 909–911, 1972.
 145. Lieberman, M., T. Sawanobori, J. M. Kootsey, E. A. Johnson. A synthetic strand of cardiac muscle. Its passive electrical properties. J. Gen. Physiol. 65: 527–550, 1975.
 146. Litchenberg, W. H., L. W. Norman, A. K. Holwell, K. L. Martin, K. W. Hewett, and R. G. Gourdie. The rate and anisotropy of impulse propagation in the postnatal terminal crest are correlated with remodeling of Cx43 gap junction pattern. Cardiovasc. Res. 45: 379–387, 2000.
 147. Li, X., and J. M. Simard. Multiple connexins form gap junction channels in rat basilar artery smooth muscle cells. Circ Res 84: 1277–1284, 1999.
 148. Little, T. L. Connexin43 and connexin40 gap junctional proteins are present in arteriolar smooth muscle and endothelium in vivo. Am. J. Physiol. 268 (Heart Circ. Physiol.): H729–H739, 1995.
 149. Liu, S., S. Taffet, L. Stoner, M. Delmar, M. L. Vallano and J. Jalife. A structural basis for the unequal sensitivity of the major cardiac and liver gap junctions to intracellular acidification: the carboxyl tail length. Biophys. J. 64: 1422–1433, 1993.
 150. Loo, L. W., M. Y. Kanemitsu and A. F. Lau. In vivo association of pp60v‐src and the gap‐junction protein connexin43 in v‐src‐transformed fibroblasts. Mol. Carcinog. 25: 187–195, 1999.
 151. Luke, R. A., J. E. Saffitz. Remodeling of ventricular conduction pathways in healed canine infarct border zones. J. Clin. Invest. 87: 1594–1602, 1991.
 152. Makowski, L. X‐ray diffraction studies of gap junction structure. Adv. Cell. Biol. 2: 119–158, 1988.
 153. Makowski, L., D. L. D. Caspar, W. C. Phillips and D. A. Goodenough. Gap junction structures II. Analysis of the x‐ray diffraction data. J. Cell. Biol. 74: 629–645, 1977.
 154. Manjunath, C. K., G. E. Goings and E. Page. Cytoplasmic surface and intramembrane components of rat heart gap junctional protein. Am. J. Physiol. 246 (Heart Circ. Physiol.): H865–H875, 1984.
 155. Massey, K. D., B. N. Minnich, and J. M. Burt. Arachidonic acid and lipoxygenase metabolites uncouple neonatal rat cardiac myocyte cell pairs. Am. J. Physiol. 263: C494–C501, 1992.
 156. Matesic, D. F., H. L. Rupp W. J. Bonney R. J. Ruch and J. E. Trosko. Changes in gap‐junction permeability, phosphorylation, and number mediated by phorbol ester and non‐phorbolester tumor promoters in rat liver epithelial cells. Mol. Care. 10: 226–236, 1994.
 157. Mazet, F., B. A. Wittenberg and D. C. Spray. Fate of intercellular junctions in isolated adult rat cardiac cells. Circ. Res. 56: 195–204, 1985.
 158. McHowat, J., K. A. Yamada, J. Wu, G. X. Yan and P. B. Corr. Recent insights pertaining to sarcolemmal phospholipid alterations underlying arrhythmogenesis in the ischemic heart. J. Cardiovasc. Electrophys. 4: 288–310, 1993.
 159. McNutt, N. S., and R. S. Weinstein. The ultrastructure of the nexus: a correlated thin‐section and freeze‐cleave study. J. Cell. Biol. 47: 666–688, 1970.
 160. Mehta, P. P. and B. Rose. Expression of connexin43 and of functional cell‐to‐cell channels in a Morris hepatoma cell line is regulated by cAMP. J. Cell Biol. 111: 154a, 1990.
 161. Mehta, P. P., M. Yamamoto and B. Rose. Transcription of the gene for the gap junctional protein connexin43 and expression of functional cell‐to‐cell channels are regulated by cAMP. Mol. Biol. Cell. 839–850, 1992.
 162. Michalke, W. and W. R. Loewenstein. Communication between cells of different type. Nature 232: 121–123, 1971.
 163. Milks, J. C., N. M. Kumar, R. Houghton et al. Topology of the 32‐kD liver gap junction protein determined by site‐directed antibody localizations. EMBO J 7: 2967–2975, 1988.
 164. Minamikawa, T., S. H. Cody and D. A. Williams. In situ visualization of spontaneous calcium waves within perfused whole rat heart by confocal imaging. Am. J. Physiol. 272 (Heart Circ. Physiol.): H236–H243, 1997.
 165. Miura, M., P. A. Boyden, and H. E. ter Keurs. Ca2+ waves during triggered propagated contractions in intact trabeculae. Am. J. Physiol. (Heart Circ. Physiol.): H266–H276, 1998.
 166. Miller, T., G. Dahl and R. Werner. Structure of a gap junction gene: connexin32. Biosci. Rep. 8: 455–464, 1988.
 167. Moore, L. K., and J. M. Burt. Antiarrythmic drugs have a minor effect on gap junction conductance. Biophys. J. 57: 246a, 1990.
 168. Moreno, A. P., B. Eghbali and D. C. Spray. Connexin32 gap junction channels in stably transfected cells. Equilibrium and kinetic properties. Biophys. J. 60: 1267–1277, 1991.
 169. Moreno, A. P., G. I. Fishman, E. C. Beyer and D. C. Spray. Voltage dependent gating and single channel analysis of heterotypic gap junction channels formed of Cx45 and Cx43. In Gap Junctions edited by Y. Kanno. Progr. Cell. Biol. 1995; 405–408.
 170. Moreno, A. P., G. I. Fishman and D. C. Spray. Phosphorylation shifts unitary conductance and modifies voltage dependent kinetics of human connexin43 gap junction channels. Biophys. J. 62: 51–53, 1992.
 171. Moreno, A. P., J. G. Laing, E. C. Beyer and D. C. Spray. Properties of gap junction channels formed of connexin45 endogenously expressed in human hepatoma (SKHepl) cells. Am. J. Physiol. 268: C356–C365, 1995.
 172. Moreno, A. P., M. B. Rook, G. I. Fishman and D. C. Spray. Gap junction channels: Distinct voltage‐sensitive and insensitive conductance states. Biophys. J. 67: 113–119, 1994.
 173. Moreno, A. P., J. C. Saez, G. I. Fishman and D. C. Spray. Human connexin43 gap junction channels: Regulation of unitary conductances by phosphorylation of the channel protein. Circ. Res. 74: 1050–1057, 1994.
 174. Morley, G. E., S. M. Taffet and M. Delmar. Intramolecular interactions mediate pH regulation of connexin43 channels. Biophys J. 70: 1294–1302, 1996.
 175. Morley, G. E., D. Vaidya, F. H. Samie, C. Lo, M. Delmar and J. Jalife. Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping. J. Cardiovasc. Electrophysiol. 10: 1361–1375, 1999.
 176. Mulder, B. J. M., P.P. de Tombe and H. E. D. J. ter Keurs. Spontaneous and propagated contractions in rat cardiac trabeculae. J. Gen. Physiol. 93: 943–961, 1989.
 177. Muller, A., T. Schaefer, W. Linke, T. Tudyka, M. Gottwald, W. Klaus and S. Dhein. Actions of the antiarrhythmic peptide AAP10 on intercellular coupling. Naunyn Schmiedebergs Arch Pharmacol. 356: 76–82, 1997.
 178. Munari‐Silem, Y., M. C. Lebrethon, I. Morand, B. Rousset and J. M. Saez. Gap junction‐mediated cell‐to‐cell communication in bovine and human adrenal cells. A process whereby cells increase their responsiveness to physiological corticotropin concentrations. J. Clin. Invest. 1429–1439, 1995.
 179. Munster, P. N. and R. Weingart. Effects of phorbol ester on gap junctions of neonatal rat heart cells. Pflugers. Arch. Eur. J. Physiol. 423: 181–188, 1993.
 180. Musil, L. S. and D. A. Goodenough. Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER. Cell 74 (6): 1065–1077, 1993.
 181. Musil, L. S. and D. A. Goodenough: Biochemical analysis of connexin43 intracellular transport, phosphorylation, and assembly into gap junctional plaques. J. Cell Biol. 115: 1357–1374, 1991.
 182. Neyton, J. and A. Trautmann. Single‐channel currents of an intercellular junction. Nature 317: 331–335, 1985.
 183. Nicholson, B. J., T. Suchyna, L. X. Xu, P. Hammernick, F. L. Cao, C. Fourtner, L. Barrio and M. V. L. Bennett. Divergent properties of different connexins expressed in Xenopus oocytes. Progr. Cell Res. 3L3014, 1993.
 184. Niggli, E., A. Rudisuli, P. Maurer and R. Weingart. Effects of general anesthetics on current flow across membranes in guinea pig myocytes. Am. J. Physiol. 1989; 256: C273–281.
 185. Noma, A. and N. Tsuboi. Dependence of junctional conductance on proton, calcium and magnesium ions in cardiac paired cells of guinea pig. J. Physiol. 382: 193–211, 1987.
 186. O'Brien, J., M. R. al‐Ubaidi and H. Ripps. Connexin35: a gap‐junctional protein expressed preferentially in the skate retina. Mol. Biol. Cell 7: 233–243, 1996.
 187. Okano, M. and Y. Yoshida. Junction complexes of endothelial cells in atherosclerosis‐prone and atherosclerosis‐resistant regions on flow dividers of brachiocephalic bifurcations in the rabbit aorta. Biorheology 31: 155–161, 1994.
 188. Osipchuk, Y. and M. Cahalan. Cell‐to‐cell spread of calcium signals mediated by ATP receptors in mast cells. Nature 359: 241–244, 1992.
 189. Page, E. and C. K. Manjunath. Communicating Junctions between cardiac cells. In: The Heart and Cardiovascular System, Scientific Foundations, Vol. 1, edited by Fozzard, E. Haber, R. B. Jennings, A. Katz, and H. Morgan, 1986: 573–600. Raven Press, NY.
 190. Paul, D. Molecular cloning of cDNA for rat liver gap junction protein. J. Cell Biol. 103: 123–134, 1986.
 191. Paul, D. L., L. Ebihara, L. J. Takemoto, K. I. Swenson and D. A. Goodenough. Connexin46, a novel lens gap junction protein, induces voltage‐gated currents in nonjunctional plasma membrane of Xenopus oocytes. J. Cell Biol. 115: 1077–1089, 1991.
 192. Paul, D. L., K. Yu, R. Bruzzone, R. L. Gimlich and D. A. Goodenough. Expression of a dominant negative inhibitor of intercellular communication in the early Xenopus embryo causes delamination and extrusion of cells. Development 121: 371–381, 1995.
 193. Penman, Splitt M., M. Y. Tsai, J. Burn and J. A. Goodship. Absence of mutations in the regulatory domain of the gap junction protein connexin43 in patients with visceroatrial heterotaxy. Heart 77: 369–370, 1997.
 194. Pepper, M. S. and P. Meda. Basic fibroblast growth factor increases junctional communication and connexin 43 expression in microvascular endothelial cells. J. Cell. Physiol 153: 196–205, 1992.
 195. Pepper, M. S., D. C. Spray, M. Chanson, R. Montesano, L. Orci and P. Meda. Junctional communication is induced in migrating capillary endothelial cells. J. Cell Biol. 109: 3027–3038, 1989.
 196. Pepper, M. S., R. Montesano, A. el Aoumari, D. Gros, L. Orci and P. Meda. Coupling and connexin 43 expression in microvascular and large vessel endothelial cells. Am. J. Physiol. C1246–C1257, 1992.
 197. Peracchia, C. and S. J. Girsch. Functional modulation of cell coupling: evidence for a calmodulin‐driven channel gate. Am. J. Physiol. 248 (Heart Circ. Physiol.): H765–H782, 1985.
 198. Peracchia, C. and L. L. Peracchia. Gap junction dynamics: reversible effects of hydrogen ions. J. Cell Biol. 87 719–727, 1980.
 199. Peracchia, C., X. Wang, L. Li and L. L. Peracchia. Inhibition of calmodulin expression prevents low pH‐induced gap junction uncoupling in Xenopus oocytes. Pflugers Arch 431: 379–387, 1996.
 200. Perkins, G. A., D. A. Goodenough and G. E. Sosinsky. Formation of the gap junction intercellular channel requires a 30 degree rotation for interdigitating two apposing connexons. J. Mol. Biol. 277: 171–177, 1998.
 201. Peters, N. S. New insights into myocardial arrhythmogenesis: distribution of gap‐junctional coupling in normal, ischaemic and hypertrophied human hearts. Clin. Sci. 90: 447–452, 1996.
 202. Peters, N. S., J. Coromilas N. J. Severs and A. L. Wit. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation 18: 988–996, 1997.
 203. Pfahnl, A., X.‐W. Zhou, J. Tian, R. Werner and G. Dahl. Mapping of the pore of gap junction channels by cysteine scanning mutagenesis. Biophys. J. 70: A31, 1996.
 204. Phelan, P., L. A. Stebbings, R. A. Baines, J. P. Bacon, J. A. Davies and C. Ford. Drosophila Shaking‐B protein forms gap junctions in paired Xenopus oocytes. Nature 391: 181–184, 1998.
 205. Polacek, D., F. Bech, J. F. McKinsey, P. F. Davies. Connexin43 gene expression in the rabbit arterial wall: effects of hypercholesterolemia, balloon injury and their combination. J. Vasc. Res. 34 (1): 19–30, 1997.
 206. Purdy, J., M. Liebermann, A. E. Roggeveen and R. Kirk. Synthetic strands of cardiac muscle: growth and physiological implications. J. Cell Biol. 65: 563–578, 1972.
 207. Rawling, D. A. and R. W. Joyner. Characteristics of the junctional regions between Purkinje and ventricular muscle cells of the canine ventricular subendocardium. Circ. Res. 60: 580–585, 1987.
 208. Razani, B., A. Schlegel and M. P. Lisanti. Caveolin proteins in signaling, oncogenic transformation and muscular dystrophy. J. Cell Sci. 2103–2109, 2000.
 209. Reaume, A. G., P. A. de Sousa, S. Kulkarni, et al. Cardiac malformation in neonatal mice lacking connexin43. Science 267: 1831–1834, 1995.
 210. Reed, K. E., E. M. Westphale, D. M. Larson, H. Z. Wang, R. D Veenstra and E. C. Beyer. Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein. J. Clin. Invest. 91: 997–1004, 1993.
 211. Revel, J.‐P. Contacts and junctions between cells. Symp. Soc. Exp. Biol. 28: 447–461.
 212. Revel, J.‐P. and M. J. Karnovsky. Hexagonal array of subunits in intercellular junctions in the mouse heart and liver. J. Cell. Biol. 33: C7–C12, 1967.
 213. Revilla, A., C. Castro and L. C. Barrio. Molecular dissection of transjunctional voltage dependence in the connexin‐32 and connexin‐43 junctions. Biophys. J. 77: 1374–1383, 1999.
 214. Robertson, J. D. The occurrence of a subunit pattern in the unit membranes of club endings in Mauthner cell synapses in goldfish brain. J. Cell Biol. 19: 201–221, 1963.
 215. Rook, M. B., H. J. Jongsma and A. C. G. van Ginneken. Properties of single gap junctional channels between isolated neonatal rat heart cells. Am. J. Physiol. 255 (Heart Circ. Physiol.): H770–H782, 1988.
 216. Rose, B. and W. R. Loewenstein. Permeability of cell junction depends on local cytoplasmic calcium activity. Nature 254: 250–252, 1975.
 217. Sáez, J. C., J. A. Connor, D. C. Spray and M. V. L. Bennett. Hepatocyte gap junctions are permeable to the second messenger, inositol 1,4,5‐trisphosphate, and to calcium ions. Proc. Natl. Acad. Sci. U.S.A. 86: 2708–2712, 1989.
 218. Sáez, J. C., W. A. Gregory, T. Watanabe, R. Dermietzel, E. L. Hertzberg, L. Reid, M. V. L. Bennett and D. C. Spray. cAMP delays disappearance of gap junctions between pairs of rat hepatocytes in primary culture. Am. J. Physiol. 257: C1–C11, 1989.
 219. Sáez, J. C., A. C. Nairn, A. J. Czernik, G. I. Fishman, D. C. Spray and E. L. Hertzberg. Phosphorylation of connexin43 and the regulation of neonatal rat cardiac gap junctions. J. Mol. Cell Cardiol. 29: 2131–2145, 1997.
 220. Saffitz, J. E., L. M. Davis, B. J. Darrow, H. L. Kanter, J. G. Laing and E. C. Beyer. The molecular basis of anisotropy: role of gap junctions. J. Cardiovasc. Electrophysiol. 6: 498–510, 1995.
 221. Saffitz, J. E., H. L. Kanter, K. G. Green, T. K. Tolley and E. C. Beyer. Tissue‐specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium. Circ. Res. 74: 1065–1070, 1994.
 222. Sanderson, M. J., A. C. and Charles, E. R. Dirksen Mechanical stimulation and intercellular communication increases intracellular Ca2+ in epithelial cells. Cell Regul. 1: 585–596, 1990.
 223. Sanderson, M. J., K. Paemeleire, A. Strahonja and L. Leyvaert. Intercellular Ca2+ signaling between glial and endothelial cells. In: Gap Junctions, edited by R. Werner. Amsterdan IOS Press. Netherlands, 1998: 261–265.
 224. Sano, T. N. Takayama and T. Shimamoto. Directional difference of conduction velocity in cardiac ventricular syncytium studied by microelectrodes. Circ. Res. 7: 262–267 1959.
 225. Seul, K. H., P. N. Tadros and E. C. Beyer. Mouse connexin40: gene structure and promoter analysis. Genomics 46: 120–126, 1997.
 226. Severs, N. J., K. S. Shovel, A. M. Slade, T. Powell, V. W. Twist, C. R. Green. Fate of gap junctions in isolated adult mammalian cardiomyocytes. Circ. Res. 65: 22–42, 1989.
 227. Segal, S. S. and B. R. Duling. Conduction of vasomotor responses in arterioles: a role for cell‐to‐cell coupling?. Am. J. Physiol. 256 (Heart Circ. Physiol.): H838–H845, 1989.
 228. Shibata, Y., C. K. Manjunath and E. Page. Differences between cytoplasmic surfaces of deep‐etched heart and liver gap junctions. Am. J. Phsysiol. 249: (Heart Circ. Physiol.) H690–H693, 1985.
 229. Simon, A. M., D. A. Goodenough and D. L. Paul. Mice lacking connexin40 have cardiac conduction abnormalities characteristic of atrioventricular block and bundle branch block. Curr. Biol. 8: 295–298, 1998.
 230. Singh, M. V., R. Bhatnagar and S. K. Malhotra. Inhibition of connexin43 synthesis by antisense RNA in rat glioma cells. Cytobios 91: 103–123, 1997.
 231. Sjostrand, F. S. and E. Anderson. Electron microscopy of the intercalated discs of cardiac muscle tissue. Experientia 9: 369–371, 1954
 232. Sjostrand, F. S., E. Andersson‐Cedergren and M. M. Dewey. The ultrastructure of the intercalated discs of frog, mouse and guinea pig cardiac muscle. Ultrast. Res. 1: 271–287, 1958.
 233. Sohl, G., J. Degen, B. Teubner and K. Willecke. The murine gap junction gene connexin36 is highly expressed in mouse retina and regulated during brain development. FEBS Lett. 426: 27–31, 1998.
 234. Spach, M. S. Changes in the topology of gap junctions as an adaptive structural response of the myocardium. Circulation 90: 1103–1106, 1994.
 235. Spach, M. S. and P. C. Dolber. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle: evidence for electrical coupling of side‐to‐side iber connections with increasing age. Circ. Res. 58: 356–371, 1986.
 236. Spach, S. and J. F. Heidlage. A multidimensional model of cellular effects on the spread of electrotonic currents and on propagating action potentials. Crit. Rev. Biomed. Eng. 20: 141–149, 1992.
 237. Spach, S. and J. F. Heidlage. The stochastic nature of cardiac propagation at a microscopic level: an electrical description of myocardial architecture and its application to conduction. Circ. Res. 76: 366–380, 1995.
 238. Spach, M. S., W. T. MillerIII and P. C. Dolber et al. The functional role of structural complexities in the propagation of depolarization in the atrium of the dog; cardiac conduction disturbances due to discontinuities of effective axial resistivity. Circ. Res. 50: 175–191, 1982.
 239. Spach, M. S., W. T. Miller 3d, E. Miller‐Jones, R. B. Warren and R. C. Barr. Extracellular potentials related to intracellular action potentials during impulse conduction in anisotropic canine cardiac muscle. Circ. Res. 45: 188–204, 1979.
 240. Sperelakis, N. and R. L. Macdonald. Ratio of transverse to longitudinal resistivities of isolated cardiac muscle fiber bundles. J. Electrocardiol. 7: 301–314, 1974.
 241. Spooner, P. M., R. W. Joyner and J. Jalife. Discontinuous Conduction in the Heart. Armonk, NY: Futura, 1997.
 242. Spray, D. C. Gap junction channels: yes, there are substates, but what does that mean?. Biophys. J. 67: 491–492, 1994.
 243. Spray, D. C. Gap junction proteins: where they live and how they die. Circ. Res. 83: 679–681, 1998.
 244. Spray, D. C. and M. V. Bennet. Physiology and pharmacology of gap junctions. Annu. Rev. Physiol. 47: 281–303, 1985.
 245. Spray, D. C. and J. M. Burt. Structure‐activity relations of the cardiac gap junction channel. Am J Physiol. 258: LC195–C205, 1990.
 246. Spray, D. C., A. C. de Carvalho Campos and M. V. Bennett. Sensitivity of gap junctional conductance to H ions in amphibian embryonic cells is independent of voltage sensitivity. Proc. Natl. Acad Sci U.S.A. 83: 3533–3536, 1986.
 247. Spray, D. C., A. L. Harris, M. V. Bennett. Gap junctional conductance is a simple and sensitive function of intracellular pH. Science 211: 712–715, 1981.
 248. Spray, D. C., A. L. Harris M. V. Bennett. Equilibrium properties of a voltage‐dependent junctional conductance. J. Gen. Physiol. 77: 77–93, 1981.
 249. Spray, D. C., A. L. Harris and M. V. Bennett. Voltage dependence of junctional conductance in early amphibian embryos. Science 204: 432–434, 1979.
 250. Spray, D. C., A. P. Moreno, J. A. Kessler and R. Dermietzel. Characterization of gap junctions between cultured leptomeningeal cells. Brain Res 568: 1–14, 1991.
 251. Spray, D. C., M. Rook, A. P. Moreno, J. C. Sáez, G. Christ, A. C. Campos de Carvalho and G. I. Fishman. Cardiovascular gap junctions: gating properties, function and dysfunction. In: Ion Channels in the Cardiovascular System: Function and Dysfunction, edited by P. M. Spooner, A. M. Brown, W. A. Catterall, G. J. Kaczorowski. H. C. Strauss, Mt. Kisco, NY: Futura 1994: 185–217.
 252. Spray, D. C. and E. Scemes. Effects of intracellular pH (and Ca2+) on gap junction channels. In: pH and Brain Function, edited by K. Kaila and B. R. Ransom. New York: John Wiley & Sons, 1998: 477–489.
 253. Spray, D. C., S. O. Suadicani, M. J. Vink and M. Srinivas. Gap junctions in the heart. In: Physiology and Pathophysiology of the Heart, edited by N. Sperelakis, Y. Kurachi, A. Terzic, M. J. Cohen 2000, San Diego, Academic Press. Pp 149–171.
 254. Spray, D. C., J. H. Stern, A. L. Harris and M. V. Bennett. Gap junctional conductance: comparison of sensitivities to H and Ca ions. Proc. Natl. Acad. Sci U.S.A. 79: 441–445, 1982.
 255. Spray, D. C. and M. J. Vink. Cardiac gap junctions as K+ (and Ca2+) channels. In: Potassium Channels in Normal and Pathological Conditions, edited by J. Vereecke, F. Verdonck and P.‐P. Van Bogaert). Leuven, Belgium: Leuven University Press, 1995; 424–427.
 256. Spray, D. C., M. J. Vink, E. Scemes, S. O. Suadicani, G. I. Fishman and R. Dermietzel. Characteristics of coupling in cardiac myocytes and CNS astrocytes cultured from wildtype and Cx43‐null mice. In: Gap Junctions, edited by R. Werner. Amsterdam The Netherlands; IOS Press, 1998: 281–285.
 257. Spray, D. C. R. L. White, A. C. de Carvalho, A. L. Harris, M. V. and Bennett. Gating of gap junction channels. Biophys. J. 45: 219–230, 1984.
 258. Srinivas, M., M. Costa, A. Fort, G. I. Fishman and D. C. Spray. Voltage dependence of macroscopic and unitary currents of gap junction channels formed by Cx50. J. Physiol. 517: 673–689, 1999.
 259. Stagg, R. B., A. M. Martinez, L. M. Green and W. H. Fletcher. cAMP regulation of connexin43 (Cx43) transcription in a variety of cell types: evidence for de novo transcription in a communication deficient mouse fibroblast cell line (CL‐1D). J. Cell Biol. 111: 155a; 1990.
 260. Steere, R. L. Electron microscopy of structural detail in frozen biological spcimens. J. Biophys. Biochem. Cytol. 3: 45–60, 1957.
 261. Steere, R. L. and J. R. Sommer. Stereo ultrastructure of nexus faces exposed by freeze‐fracturing. J. Microsc. (Paris) 15: 205–218; 1972.
 262. Suadicani, S. O., M. J. Vink and D. C. Spray. Slow intercellular Ca2+ signaling in wild type and Cx43‐null neonatal cardiac myocytes. Am. J. Physiol. (Heart Circ Physiol) 279: H3076–3088, 2000.
 263. Suchyna, T. M., L. X. Xu, F. Gao, C. R. Fourtner, B. J. Nicholson. Identification of a proline residue as a transduction element involved in voltage gating of gap junctions. Nature 365: 847–849, 1993.
 264. Sullivan, R. and C. W. Lo. Expression of connexin43/beta‐galactosidase fusion protein inhibits gap junctional communication in NIH3T3 cells. J. Cell. Biol. 130: 419–429, 1995.
 265. Sullivan, R., C. Ruangvoravat, D. Joo, J. Morgan, B. L. Wang, X. K. Wang, and C. W. Lo. Structure, sequence and expression of the mouse Cx43 gene encoding connexin43. Gene 130: 191–199, 1993.
 266. Swenson, K. I., H. Piwnica‐Worms, H. McNamee and D. L. Paul. Tyrosine phosphorylation of the gap junction protein connexin43 is required for the pp60v‐src‐induced inhibition of communication. Cell Regul. 1: 989–1002, 1990.
 267. Takens‐Kwak, B. R. and H. J. Jongsma. Cardiac gap junctions: three distinct single channel conductances and their modulation by phosphorylating treatments. Plugers Arch. 422: 198–200, 1992.
 268. Takens‐Kwak, B. R., H. J. Jongsma, M. B. Rook and A. C. Van Ginneken. Mechanism of heptanol‐induced uncoupling of cardiac gap junctions: a perforated patch‐clamp study. Am J Physiol 262: C1531–C1538, 1992.
 269. ter Keurs, H. E. D. J. and Y. M. Zhang. Triggered propagated contractions and arrhythmias caused by acute damage to cardiac muscle. In: Discontinuous Conduction in the Heart. edited by P. M. Spooner, R. W. Joyner and J. Jalife, eds. Armonk, NY Futura 1997: 223–240.
 270. Thomas, S. A., R. B. Schuessler, C. I. Berul, M. A. Beardslee E. C. Beyer, M. E. Mendelsohn and J. E. Saffitz. Disparate effects of deficient expression of connexin43 on atrial and ventricular conduction. Circulation 97: 686–691, 1998.
 271. Toyofuku, T., M. Yabuki, K. Otsu, T. Kuzuya, M. Hori and M. Tada. Direct association of the gap junction protein connexin‐43 with ZO‐1 in cardiac myocytes. J. Biol Chem. 273: 12725–12731, 1998.
 272. Tsien, R. H. W. and R. Weingart. Inotropic effect of cyclic AMP in calf ventricular muscle studied by a cut end method. J Physiol. (Lond) 260: 117–141, 1976.
 273. Traub, O., R. Eckert, H. Lichtenberg‐Frate, C. Elfgang, B. Bastide, K. H. Scheidtmann and D. F. Hulser, K. Willecke. Immunochemical and electrophysiological characterization of murine connexin40 and‐43 in mouse tissues and transfected human cells. Eur. J Cell Biol. 64: 101–112, 1994.
 274. ter Keurs, H. E., Y. M. Zhang, A. W. Davidoff, P. A. Boyden, V. Wakayama and M. Miura. Damage induced arrhythmias: mechanisms and implications. Canad. J. Physiol. Pharmacol. 79: 73–81, 2001.
 275. Tibbits, T. T., D. L. D. Caspar, W. C. Phillips and D. A. Goodenough. Diffraction diagnosis of protein folding in gap junction connexons. Biophys. J. 57: 1025–1036, 1990.
 276. Tsien, R. W. and R. Weingart. Inotropic effect of cyclic AMP in calf ventricular muscle studied by a cut end method. J. Physiol. (Lond.) 260: 117–141, 1976.
 277. Turin, L. and A. E. Warner. Intracellular pH in early Xenopus embryos: its effect on current flow between blastomeres. J. Physiol. 300: 489–504, 1980.
 278. Unger, V. M., N. M. Kumar, N. B. Gilula and M. Yeager. Expression, two‐dimensional crystallization and electron cryocrystallography of recombinant gap junction membrane channels. J. Struct. Biol. 128: 98–105, 1999.
 279. Valiunas, V., F. F. Bukauskas and R. Weingart. Conductances and selective permeability of connexin43 gap junction channels examined in neonatal rat heart cells. Circ. Res. 80: 708–719, 1997.
 280. Valiunas, V., R. Weingart and P. R. Brink. Formation of heterotypic gap junction channels by connexins 40 and 43. Circ. Res. 86: E42–E49, 2000.
 281. Van Rijen, H. V., M. J. van Kempen Postma, S. and H. J. Jongsma. Tumour necrosis factor alpha alters the expression of connexin43, connexin40, and connexin37 in human umbilical vein endothelial cells. Cytokine 10: 258–264, 1998.
 282. Van Kempen, M. J., J. L. Vermeulen, A. F. Moorman, D. Gros, D. L. Paul and W. H. Lamers. Developmental changes of connexin40 and connexin43 mRNA distribution patterns in the rat heart. Cardiovasc. Res. 32: 886–900, 1996.
 283. Veenstra, R. D. and R. L. DeHaan. Measurement of single channel currents from cardiac gap junctions. Science 233: 972–974, 1986.
 284. Veenstra, R. D., H‐Z Wang, E. Beyer and P. R. Brink. Selective dye and ionic permeability of gap junction channels formed by connexin45. Circ. Res. 75: 483–490, 1994.
 285. Veenstra, R. D., H. Z. Wang, E. C. Beyer, S. V. Ramanan and P. R. Brink. Connexin37 forms high conductance gap junction channels with subconductance state activity and selective dye and ionic permeabilities. Biophys. J. 66: 1915–1928, 1994.
 286. Verheule, S., M. J. Van Kempen, P. H. teWelscher, B. R. Kwak and H. J. Jongsma. Characterization of gap junction channels in adult rabbit atrial and ventricular myocardium. Circ. Res. 80: 673–681, 1997.
 287. Verselis, V. K., C. S. Ginter and T. A. Bargiello. Opposite voltage gating polarities of two closely related connexins. Nature 368: 348–351, 1994.
 288. Waltzman, M. and D. C. Spray. Anionic permeability of Cx37 channels is vanishingly low. Biophys. J. 68: A227, 1995.
 289. Waltzman, M. N. and D. C. Spray. Exogenous expression of connexins for physiological characterization of channel properties: comparison of methods and results. In: Intercellular Communication Through Gap Junctions, edited by Y. Kanno, K. Kataoka, Y. Shiba, Y. Shibata and T. Shimazu. Progr. Cell Res. 4: 9–17, 1995.
 290. Wang, H. H. Z. and R. D. Veenstra. Monovalent ion selectivity sequences of the rat connexin43 gap junction channel. J. Gen. Physiol. 109: 491–507, 1997.
 291. Wang, X. G. and C. Peracchia. Chemical gating of heteromeric and heterotypic gap junction channels. J Membr Biol 162: 169–176, 1998.
 292. Wang, X. G. and C. Peracchia. Positive charges of the initial C‐terminus domain of Cx32 inhibit gap junction gating sensitivity to CO2. Biophys. J. 73: 798–806, 1997.
 293. Warn‐Cramer, B., J. G. T. Cottrell, J. M. Burt, A. F. Lau. Regulation of connexin‐43 gap junctional intercellular communication by mitogen‐activated protein kinase. J. Biol. Chem. 273: 9188–9196, 1998.
 294. Watts, S. W. and R. C. Webb. Vascular gap junctional communication is increased in mineralocorticoid‐salt hypertension. Hypertension 28: 888–893, 1996.
 295. Weidmann, S. The electrical constants of Purkinje fibres. J. Physiol. (Lond). 127: 348–360, 1952.
 296. Weiner, E. C. and W. R. Loewenstein. Correction of cell‐cell communication defect by introduction of a protein kinase into mutant cells. Nature 305: 433–435, 1983.
 297. Werner, R., T. Miller, R. Azarnia and G. Dahl. Translation and functional expression of cell‐cell channel mRNA in Xenopus oocytes. J. Membr Biol 87: 253–268, 1985.
 298. Wier, W. G., H. E. ter Keurs, E. Maban, W. D. Gao and C. W. Balke. Ca2+ ‘sparks’ and waves in intact ventricular muscle resolved by confocal imaging. Circ. Res. 81: 462–469, 1997.
 299. White, R. L., J. E. Doeller, V. K. Verselis and B. A. Wittenberg. Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca2+. J. Gen. Physiol. 95: 1061–1075, 1990.
 300. White, T. W., R. Bruzzone, S. Wolfram, D. L. Paul and D. A. Goodenough. Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins. J. Cell Biol. 125: 879–892, 1994.
 301. White, R. L., D. C. Spray, A. C. Campos de Carvalho, B. A. Wittenberg and M. V. Bennett. Some electrical and pharmacological properties of gap junctions between adult venticular myocytes. Am. J. Physiol. 249: C447–C455, 1985.
 302. Wilders, R. and H. J. Jongsma. Limitations of the dual voltage clamp method in assaying conductance and kinetics of gap junction channels. Biophys. J. 63: 942–953, 1992.
 303. Willecke, K., O. Traub, J. Look, R. Stutenkemper and R. Dermietzel. Different protein components contribute to the structure and function of hepatic gap junctions. Gap Junctions, edited by E. L. Hertzberg, and R. G. Johnson. New York: Alan R. Liss, 1988: 41–52.
 304. Woodbury, J. W. and W. E. Crill. On the problem of impulse conduction in the atrium. Nervous Inhibition, edited by E. Flovey. New York: Pergamon, 1961: 124–135.
 305. Wu, J., J. McHowat, J. E. Saffitz, K. A. Yamada and P. B. Corr. Inhibition of gap junctional conductance by long‐chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia. Circ. Res. 72: 879–889, 1993.
 306. Xie, H. Q. and V. W. Hu. Modulation of gap junctions in senescent endothelial cells. Exp. Cell Res. 214: 172–176, 1994.
 307. Yaeger, M. and N. B. Gilula. Membrane topology and quaternary structure of cardiac gap junction ion channels. J. Mol. Biol. 223: 929–948, 1992.
 308. Yaeger, M. and B. J. Nicholson. Structure of gap junction intercellular channels. Curr. Opin. Struct. Biol. 6: 183–192, 1996.
 309. Yamada, K. A., J. McHowat, G. X. Yan, K. Donahue, J. Peirick, A. G. Kleber and P. B. Corr. Cellular uncoupling induced by accumulation of long‐chain acylcarnitine during ischemia. Cir. Res. 74: 83–95, 1994.
 310. Yancey, S. B., S. A. John, R. Lal, B. J. Austin and J‐P Revel. The 43‐kD polypeptide of heart gap junctions: immunolocalization, topology and functional domains. J. Cell. Biol. 108: 2241–2254, 1989.
 311. Yancey, S. B., B. J. Nicholson and J. P. Revel. The dynamic state of liver gap junctions. J. Supramol. Struct. Cell Biochem. 221–232, 1981.
 312. Yeh, H. I., F. Lupu, E. Dupont and N. J. Severs. Upregulation of connexin43 gap junctions between smooth muscle cells after balloon catheter injury in the rat carotid artery. Arterioscler Thromb. Vasc. Biol. 17: 3174–3184, 1997.
 313. Yeh, H. I., E. Dupont, S. Coppen, S. Rothery and N. J. Severs. Gap junction localization and connexin expression in cytochemically identified endothelial cells of arterial tissue. J. Histochem. Cytochem. 45: 539–550, 1997.
 314. Yu W., G. Dahl and R. Werner. The connexin43 gene is responsive to oestrogen. Proc. R. Soc. Lond. B. 255: 125–132, 1994.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

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