Electrical Coupling at Gap Junctions in the Heart

Cardiac muscle is not a true electrical syncytium. Rather, it is composed of individual cells, each in vested with a continuous lipid bilayer which provides a considerable degree of electrical insulation. Electrical activation of the heart requires intercellular transfer of current, a process that can only occur at gap junctions [2]. Thus, the number, size, and distribution of gap junctions are important determinants of impulse propagation in cardiac muscle. Furthermore, alterations in the structure or function of gap junctions can give rise to conduction disturbances that may contribute to arrhythmogenesis.

There is an intimate structural, functional, and spatial relationship between gap junctions and mechanical junctions in cardiac myocytes. Cardiac myocytes are connected by extremely large intercellular junctions, which, presumably, have evolved to subserve the specialized electrical and contractile function of these cells. For example, because cardiac my-ocytes contract, they require more extensive and robust adhesion junctions than noncontractile cells in other solid organs. It is no surprise, therefore, that adherens junctions and desmosomes, organelles responsible for physically connecting one cardiac my-ocyte to another, are highly concentrated at the ends of individual cells where they form elaborate complexes that can be readily identified at the light microscopic level of resolution and which have been given a specific name - the intercalated disk. Intercalated disks are composed mainly of arrays of adherens junctions, each located at the end of a row of sar-comeres. These junctions act as bridges which link actin filaments within sarcomeres of neighboring cells. Interspersed among the adherens junctions are desmosomes, which also provide mechanical coupling and link cell-cell adhesion junctions to desmin filaments of the cytoskeleton. Because electrical activation of the heart requires intercellular transfer of current, cardiac myocytes also have a special requirement for extensive electrical coupling. Indeed, gap junctions interconnecting ventricular myocytes are among the largest in living systems, presumably reflecting a need for many low-resistance electrical communicating channels between cells to ensure safe conduction.

However, membrane regions containing gap junctions are rigid and nonfluid because of the high concentration of protein within the lipid bilayer, and as a result, these regions are vulnerable to shear stress. It is no surprise, therefore, that gap junctions in cardiac myocytes are located at intercalated disks where they are virtually surrounded by mechanical junctions. Presumably, these mechanical junctions act like "spot welds" to create membrane domains that are protected from shear stress caused by contractile activities of neighboring cells and which facilitate assembly and maintenance of large arrays of intercellular electrical channels. On the basis of these and related observations, we have proposed that the extent to which cardiac myocytes can become electrically coupled depends on their degree of mechanical coupling [3]. As shown in Fig. 5.1, this hypothesis provides a mechanistic link between contractile dysfunction and electrical dysfunction in the cell-cell junction cardiomyopathies. A genetic defect in a protein in cell-cell adhesion junctions may lead to unstable mechanical linkage between cells and/or discontinuities between cell-cell junctions and the cardiac myocyte cytoskele-ton. Such defective mechanical linkage may lead to diminished force transmission which, in turn, can lead to myocyte injury, tissue remodeling, and a clinical picture characterized by contractile dysfunction and cardiomyopathy. In addition, abnormal mechanical linkage can destabilize the sarcolemmas of adjacent cells. This may lead to gap junction remodeling which could contribute to slow conduction, arrhythmias, and sudden death in patients with cell-cell junction cardiomyopathies. As briefly presented below, we have tested this hypothesis through multiple approaches. First, we have characterized the distribution of intercalated disk proteins in cardiac tissues from patients and have shown that, as a general rule, the cell-cell junction cardiomyopathies are associated with remodeling of gap junctions. Second, we have identified electrophysiological phenotypes in genetically engineered mouse models of the human cardiomyopathies. Third, we have elucidated signaling pathways that coordinately regulate expression of mechanical and electrical junction proteins in cardiac myocytes in response to mechanical stress.

Linking Electrical and Contractile Dysfunction in the Cell-Cell Junction Cardiomyopathies

Linking Electrical and Contractile Dysfunction in the Cell-Cell Junction Cardiomyopathies

Abnormal Mechanical Linkage at Cell-Cell Junctions and/or Discontinuities Between Junctions and the Cytoskeleton

Myocyte Injury Myocardial Remodeling

Contractile Dysfunction Cardiomyopathy

Electrical Dysfunction Slow Conduction Arrhythmias Sudden Death

Myocyte Injury Myocardial Remodeling

Contractile Dysfunction Cardiomyopathy

Electrical Dysfunction Slow Conduction Arrhythmias Sudden Death

Fig. 5.1 • A flow chart illustrating a proposed mechanism linking electrical and contractile dysfunction in the cell-cell junction cardiomyopathies

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