Gap Junctions and Connexin Expression in Human Heart Disease

Abstract

Sequential contraction of the cardiac chambers depends on orderly spread of the wave of electrical excitation from one cardiomyocyte to the next, throughout the heart. As discussed in earlier chapters of this volume, the pathways enabling this cell-to-cell current flow are formed by the gap junctions that link individual cardiomyocytes into a functional syncytium. Gap junctions are essentially clusters of transmembrane channels that span the paired plasma membranes of neighboring cells, linking their cytoplasmic compartments together to form pathways for direct cell-to-cell communication. The component proteins of the gap-junctional channel, connexins, are assembled into hexamers which form hemi-channels termed connexons, the complete channel being formed by the docking of a pair of connexons across the adjacent plasma membranes. Twenty different connexin genes have now been identified in the human (Willecke et al., 2001), and most tissues, including those of the cardiovascular system, express two or more connexin isoforms. Three principal isoforms — connexin43, connexin40 and connexin45 — are expressed in cardiomyocytes (reviews, Beyer et al., 1997; Severs, 1999; Severs et al., 2001), and further isoforms such as connexin46 (Paul et al., 1991) and connexin57 (Manthey et al., 1999) may also be present in trace amounts. Gapjunctional channels composed of different connexins exhibit distinctive biophysical properties in vitro (review, Bruzzone et aI., 1996), and studies on transgenic mice demonstrate that the precise functional properties of gap junctions in vivo may depend in part on the specific connexins from which they are constructed, though there is also considerable capacity for functional compensation of one connexin isoform by another (Kirchhoff et al., 2000; KrUger et al., 2000; Plum et al., 2000; Tamaddon et al., 2000; van ijen et al., 2001). Different subsets of cardiomyocyte express different combinations and relative quantities of connexins 43, 40 and 45, potentially providing for regional differentiation of electrophysiological properties. The concept has thus developed that gap junction organization and spatially defined patterns of connexin expression may preside over the precisely or chestrated patterns of current flow that govern the normal heart rhythm.