Pathophysiology of gap junctions in heart disease.
Electrical coupling between cardiac muscle cells is mediated by specialized sites of plasma membrane interaction termed gap junctions. These junctions consist of clusters of membrane channels that directly link the cytoplasmic compartments of neighboring cells. Each gap-junctional channel consists of two connexons, one from each of the interacting plasma membranes, extending across the narrow extracellular gap. Connexons are constructed from connexins, a multigene family of conserved proteins. Different connexins confer specific electrophysiologic characteristics on the assembled channel protein. The major connexin of the mammalian heart is connexin43, although other types of connexins are also expressed, notably connexin40 in myocytes of the atrioventricular conduction system. Confocal laser scanning microscopy of anti-connexin43 immunolabeled samples reveals two major abnormalities in myocardial gap junctions in ischemic heart disease: loss of the usual ordered distribution of gap junctions at border zones adjacent to infarct scars, and reduction in the quantity of connexin43 gap junctions in myocardium distant from the infarct. These and other changes reported in myocardial gap-junctional communication pathways following infarction may result in heterogeneous anisotropic conduction and reduced conduction velocity, thereby forming a proarrhythmic substrate. Current evidence suggests that reduction in connexin43 content is a general pathogenetic feature of cardiac disease, and that changes in the expression levels of other connexin types may contribute to altered electrophysiologic function in the diseased heart.
Severs
N J
NJ
Department of Cardiac Medicine, National Heart and Lung Institute, London, United Kingdom.
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000918:Antibody Specificity; D002462:Cell Membrane / Q000378:metabolism; D017630:Connexins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D017629:Gap Junctions / Q000502:physiology*; D006331:Heart Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012016:Reference Values
D000906:Antibodies; D017630:Connexins; D007473:Ion Channels