Regulation of gap junctions

Abstract

Gap junctions are composed of intercellular channels that allow for electrotonic and metabolic coupling between adjacent cells. Each channel is an oligomeric assembly of homologous proteins, called connexins (Cxs), which are encoded by a gene family. Gap junctions can be regulated at multiple levels, from the expression of their genes to the assembly of their structural components and the functional state of the channels. The regulation of three different connexins was studied in vitro in different cell types and in vivo during the ontogeny of the rat liver and pineal gland. Studies in vitro indicated that a tumor promoting phorbol ester induced a rapid phosphorylation of Cx43 via protein kinase C. Phosphoamino acid analysis and two dimensional tryptic maps of {dollar}\sp{lcub}32{rcub}{dollar}P-labelled Cx43 indicated that TPA induced differential phosphorylation of seryl residues in two phosphorylated forms of Cx43, P{dollar}\sb2{dollar} and P{dollar}\sb3,{dollar} as compared to control. These changes in the phosphorylation state of Cx43 were temporally related to loss of coupling which is believed to be an early event during tumor promotion. Ca{dollar}\sp{lcub}2+{rcub}{dollar}-dependent cell adhesion was found to be essential for formation of gap junctions but not for phosphorylation of Cx43. The glucocorticoid, dexamethasone, up-regulated levels of Cx32 in primary cultures of hepatocytes as it has been shown for other hepatic functional genes. In primary cultures of pinealocytes, which express Cx26, noradrenaline, the neurotransmitter released by the sympathetic nerve terminals onto the pineal gland, up-regulated the levels of Cx26 over a time course of a few hours, and increased coupling between pinealocytes. Studies in vivo demonstrated a developmental regulation of pineal astrocyte gap junctions formed by Cx43. Developmental regulation of hepatocyte gap junctions formed by Cx32 alone or in combination with Cx26 was also observed. Cx43 expressed by non-parenchymal liver cells, however, did not show significant changes during development. In each organ, adult levels and pattern of distribution of Cxs expressed by parenchymal cells were attained at a time when the organ reaches functional maturity. These results indicate and support the notion that gap junctions can be developmentally and differentially regulated at different levels.