The Molecular Basis of Anisotropy: Role of Gap Junctions

Role of Gap Junctions in Anisotropic Conduction. Electrical activation of the heart requires transfer of current from one discrete cardiac myocyte to another, a process that occurs at gap junctions. Recent advances in knowledge have established that, like most differentiated cells, individual cardiac myocytes express multiple gap junction channel proteins that are members of a multigene family of channel proteins called connexins. These proteins form channels with unique biophysical properties. Furthermore, functionally distinct cardiac tissues such as the nodes and bundles of the conduction system and atrial and ventricular muscle express different combinations of connexins. Myocytes in these tissues are interconnected by gap junctions that differ in a tissue‐specific manner in terms of their number, size, and three‐dimensional distribution. These observations suggest that both molecular and structural aspects of gap junctions are critical determinants of the anisotropic conduction properties of different cardiac tissues. Expression of multiple connexins also creates the possibility that “hybrid” channels composed of more than one connexin protein type can form, thus greatly increasing the potential for fine control of intercellular ion flow and communication within the heart.

[1]  D. Paul,et al.  Connexin46, a novel lens gap junction protein, induces voltage-gated currents in nonjunctional plasma membrane of Xenopus oocytes , 1991, The Journal of cell biology.

[2]  A. Noma,et al.  Dependence of junctional conductance on proton, calcium and magnesium ions in cardiac paired cells of guinea‐pig. , 1987, The Journal of physiology.

[3]  R. Bruzzone,et al.  Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins , 1994, The Journal of cell biology.

[4]  J. Saffitz,et al.  Distinct patterns of connexin expression in canine Purkinje fibers and ventricular muscle. , 1993, Circulation research.

[5]  A. Moreno,et al.  Human connexin43 gap junction channels. Regulation of unitary conductances by phosphorylation. , 1994, Circulation research.

[6]  M. Janse,et al.  Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. , 1989, Physiological reviews.

[7]  J. Saffitz,et al.  Expression of multiple connexins in cultured neonatal rat ventricular myocytes. , 1995, Circulation research.

[8]  J. Saffitz,et al.  Distinct gap junction protein phenotypes in cardiac tissues with disparate conduction properties. , 1994, Journal of the American College of Cardiology.

[9]  P. Poole‐Wilson,et al.  Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts. , 1993, Circulation.

[10]  K. Fischbeck,et al.  Connexin mutations in X-linked Charcot-Marie-Tooth disease. , 1993, Science.

[11]  C. Green,et al.  Cardiac myocyte gap junctions: evidence for a major connexon protein with an apparent relative molecular mass of 70,000. , 1990, Journal of cell science.

[12]  R. Lal,et al.  The 43-kD polypeptide of heart gap junctions: immunolocalization, topology, and functional domains , 1989, The Journal of cell biology.

[13]  N. Severs.  Pathophysiology of Gap Junctions in Heart Disease , 1994, Journal of cardiovascular electrophysiology.

[14]  W H Lamers,et al.  Spatial distribution of connexin43, the major cardiac gap junction protein, in the developing and adult rat heart. , 1991, Circulation research.

[15]  T. Steinberg,et al.  Evidence that the gap junction protein connexin-43 is the ATP-induced pore of mouse macrophages. , 1991, The Journal of biological chemistry.

[16]  M. Bennett,et al.  Biophysics of gap junctions. , 1992, Seminars in cell biology.

[17]  W H Lamers,et al.  Immunohistochemical delineation of the conduction system. I: The sinoatrial node. , 1993, Circulation research.

[18]  D. Paul,et al.  Topological distribution of two connexin32 antigenic sites in intact and split rodent hepatocyte gap junctions , 1988, The Journal of cell biology.

[19]  D. Geselowitz,et al.  The Discontinuous Nature of Propagation in Normal Canine Cardiac Muscle: Evidence for Recurrent Discontinuities of Intracellular Resistance that Affect the Membrane Currents , 1981, Circulation research.

[20]  J E Saffitz,et al.  Remodeling of ventricular conduction pathways in healed canine infarct border zones. , 1991, The Journal of clinical investigation.

[21]  C. Green,et al.  Topological analysis of the major protein in isolated intact rat liver gap junctions and gap junction-derived single membrane structures. , 1987, The Journal of biological chemistry.

[22]  J. Saffitz,et al.  Cardiac myocytes express multiple gap junction proteins. , 1992, Circulation research.

[23]  D. Paul,et al.  Connexin43: a protein from rat heart homologous to a gap junction protein from liver , 1987, The Journal of cell biology.

[24]  P. Micevych,et al.  Distribution of mRNAs coding for liver and heart gap junction proteins in the rat central nervous system , 1991, The Journal of comparative neurology.

[25]  D. Spray,et al.  Trypanosome infection decreases intercellular communication between cardiac myocytes , 1993 .

[26]  M Delmar,et al.  Immunohistochemical Localization of Gap Junction Protein Channels in Hamster Sinoatrial Node in Correlation with Electrophysiologic Mapping of the Pacemaker Region , 1994, Journal of cardiovascular electrophysiology.

[27]  L. Makowski,et al.  Gap junction structures: Analysis of the x-ray diffraction data , 1977, The Journal of cell biology.

[28]  R. Garfield,et al.  Modulation of cell-to-cell coupling between myometrial cells of the human uterus during pregnancy. , 1992, American journal of obstetrics and gynecology.

[29]  K. Willecke,et al.  Immunochemical and electrophysiological characterization of murine connexin40 and -43 in mouse tissues and transfected human cells. , 1994, European journal of cell biology.

[30]  K E Muffly,et al.  Structural Remodeling of Cardiac Myocytes in Patients With Ischemic Cardiomyopathy , 1992, Circulation.

[31]  J. Saffitz,et al.  Multiple connexins colocalize in canine ventricular myocyte gap junctions. , 1993, Circulation research.

[32]  J E Saffitz,et al.  Distribution and Three‐Dimensional Structure of Intercellular Junctions in Canine Myocardium , 1989, Circulation research.

[33]  M. Pressler,et al.  Cloning of a gap junctional protein from vascular smooth muscle and expression in two-cell mouse embryos. , 1990, The Journal of biological chemistry.

[34]  P. Corr,et al.  Inhibition of gap junctional conductance by long-chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia. , 1993, Circulation research.

[35]  J. Revel,et al.  Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. , 1991, The Biochemical journal.

[36]  R. P. Thompson,et al.  The spatial distribution and relative abundance of gap-junctional connexin40 and connexin43 correlate to functional properties of components of the cardiac atrioventricular conduction system. , 1993, Journal of cell science.

[37]  D. Ganten,et al.  Gap junction protein connexin40 is preferentially expressed in vascular endothelium and conductive bundles of rat myocardium and is increased under hypertensive conditions. , 1993, Circulation research.

[38]  P. Brink,et al.  Selective dye and ionic permeability of gap junction channels formed by connexin45. , 1994, Circulation research.

[39]  C. Ginter,et al.  Opposite voltage gating polarities of two closely related onnexins , 1994, Nature.

[40]  M. Yeager,et al.  Membrane topology and quaternary structure of cardiac gap junction ion channels. , 1992, Journal of molecular biology.

[41]  A. Moreno,et al.  Phosphorylation shifts unitary conductance and modifies voltage dependent kinetics of human connexin43 gap junction channels. , 1992, Biophysical journal.

[42]  R. Veenstra,et al.  Multiple connexins confer distinct regulatory and conductance properties of gap junctions in developing heart. , 1992, Circulation research.

[43]  J. Haefliger,et al.  Connexin40, a component of gap junctions in vascular endothelium, is restricted in its ability to interact with other connexins. , 1993, Molecular biology of the cell.

[44]  D. Paul.  Molecular cloning of cDNA for rat liver gap junction protein , 1986, The Journal of cell biology.

[45]  E. Beyer,et al.  Characterization of gap junction channels in A7r5 vascular smooth muscle cells. , 1991, The American journal of physiology.

[46]  J E Saffitz,et al.  Tissue-specific determinants of anisotropic conduction velocity in canine atrial and ventricular myocardium. , 1994, Circulation research.

[47]  B L Langille,et al.  Cardiac malformation in neonatal mice lacking connexin43. , 1995, Science.

[48]  A. Moorman,et al.  Restricted distribution of connexin40, a gap junctional protein, in mammalian heart. , 1994, Circulation research.

[49]  Capelle,et al.  Slow conduction in the infarcted human heart. 'Zigzag' course of activation. , 1993, Circulation.

[50]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .

[51]  T. Opthof.  Gap Junctions in the Sinoatrial Node: , 1994, Journal of cardiovascular electrophysiology.

[52]  K. Willecke,et al.  Comparative characterization of the 21-kD and 26-kD gap junction proteins in murine liver and cultured hepatocytes , 1989, The Journal of cell biology.

[53]  L. Orci,et al.  Differential expression of gap junction connexins in endocrine and exocrine glands. , 1993, Endocrinology.

[54]  R. Veenstra,et al.  Unique conductance, gating, and selective permeability properties of gap junction channels formed by connexin40. , 1995, Circulation research.

[55]  M Delmar,et al.  Gap junctional channels in adult mammalian sinus nodal cells. Immunolocalization and electrophysiology. , 1992, Circulation research.

[56]  D. S. Crow,et al.  Evidence that heart connexin43 is a phosphoprotein. , 1991, Journal of molecular and cellular cardiology.

[57]  J. Saffitz,et al.  Expression of Multiple Gap Junction Proteins in Human Fetal and Infant Hearts , 1994, Pediatric Research.

[58]  N. Dekel,et al.  Phosphorylation and expression of connexin-43 ovarian gap junction protein are regulated by luteinizing hormone. , 1994, The Journal of biological chemistry.

[59]  R. Veenstra,et al.  Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein. , 1993, The Journal of clinical investigation.

[60]  W H Lamers,et al.  Immunohistochemical delineation of the conduction system. II: The atrioventricular node and Purkinje fibers. , 1993, Circulation research.