The molecular mechanisms of gap junction remodeling

Abstract

c b o i m u C r p C T l t p c t m Localization of connexin43 in the heart In 1967, Revel and Karnovsky first described an aggregate f membrane associated particles that, while looking like hey blocked the extracellular space, allowed the tracer anthanum hydroxide to pass through small gaps between he aggregates and named this cluster of particles the “gap unction.” In the heart, they described these structures to be rimarily at the long ends of the cells, identified as the ntercalated disk (ID). Further studies by Page and his coleague noted the presence of a “fuzzy coat” under the gap unctions, giving rise to the speculation that the extracellular ggregates crossed the myocyte membrane and anchored ithin the cell. From these early studies grew a new field of esearch on what these aggregates were made of and how hey worked. In cardiac studies, the primary component of ardiac gap junctions was identified as a 43-kD protein, subsequently named Connexin43 (Cx43). Studies showed that unlike liver cells, where the hepatocyte connexin, connexin 32, was localized all over the cells, in the myocytes of the heart, connexins were preferentially localized to the ends of cells at the IDs such that images showing longitudinal sections of myocytes gave a straight line of staining that was evident at myocyte ends (Figure 1A). Transverse images show that Cx43 does not cover the entire ends of the myocytes; rather it is positioned in a ring around the edges of the ID (Figure 1B). This pattern has been shown in the hearts of mice, dogs, and humans, indicating that this ighly organized pattern is conserved across species. Unerstanding of the function of gap junctions as conduits for lectrical current led to hypotheses that the localization of x43 in the heart was important for the normal anisotropic onduction of the heart. Interest in the role of gap junctions in heart disease was iqued when images of diseased hearts stained for Cx43 howed that cardiac pathologies were associated with a hange in the normal pattern of Cx43 in the ventricular yocardium. Rather than being localized at the ID, Cx43 n human hearts after a myocardial infarction was found on