Calmodulin-Mediated Regulation of Gap Junction Channels
Camillo Peracchia
Abstract
Evidence that neighboring cells uncouple from each other as one dies surfaced in the late 19th century, but it took almost a century for scientists to start understanding the uncoupling mechanism (chemical gating). The role of cytosolic free calcium (Ca 2+ i ) in cell-cell channel gating was first reported in the midsixties. In these studies, only micromolar [Ca 2+ ] i were believed to affect gating-concentrations reachable only in cell death, which would discard Ca 2+ i as a fine modulator of cell coupling. More recently, however, numerous researchers, including us, have reported the effectiveness of nanomolar [Ca 2+ ] i . Since connexins do not have high-affinity calcium sites, the effectiveness of nanomolar [Ca 2+ ] i suggests the role of Ca-modulated proteins, with calmodulin (CaM) being most obvious. Indeed, in 1981 we first reported that a CaM-inhibitor prevents chemical gating. Since then, the CaM role in gating has been confirmed by studies that tested it with a variety of approaches such as treatments with CaM-inhibitors, inhibition of CaM expression, expression of CaM mutants, immunofluorescent co-localization of CaM and gap junctions, and binding of CaM to peptides mimicking connexin domains identified as CaM targets. Our gating model envisions Ca 2+ -CaM to directly gate the channels by acting as a plug (-Cork gating model), and probably also by affecting connexin conformation.