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Calmodulin-Mediated Regulation of Gap Junction Channels

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...

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Detalles Bibliográficos
Autor principal: Peracchia, Camillo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014422/
https://www.ncbi.nlm.nih.gov/pubmed/31940951
http://dx.doi.org/10.3390/ijms21020485
Descripción
Sumario: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 mid-sixties. 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.