Connexin43 phosphorylation: structural changes and biological effects

Abstract

SYNOPSIS Vertebrate gap junctions, composed of proteins from the connexin gene family, play critical roles in embryonic development, coordinated contraction of excitable cells, tissue homeostasis, normal cell growth and differentiation. Phosphorylation of connexin43, the most abundant and ubiquitously expressed connexin, has been implicated in the regulation of gap junctional communication at several stages of the connexin “life cycle” including hemichannel oligomerization, export of the protein to the plasma membrane, hemichannel activity, gap junction assembly, gap junction channel gating and connexin degradation. Consistent with a short (1−5 h) protein half-life, connexin43 phosphorylation is dynamic and changes in response to activation of many different kinases. This review assesses our current understanding of the effects of phosphorylation on connexin43 structure and function that in turn regulate gap junction biology with an emphasis on events occurring in heart and skin.

Functional interaction between TRPC1 channel and connexin-43 protein: a novel pathway underlying S1P action on skeletal myogenesis

“…These data gain support by the increasing evidence in the literature, showing the critical role played by phosphorylation events in the gap junction turnover [22,29,44]. In particular, several kinases, including PKC isoforms, casein kinase, mitogen-activated protein kinase (MAPK) and c-scr kinase, have been shown to phosphorylate the cytosolic carboxyl-terminal domain of Cx43 and mediate the protein internalization and degradation through the activation of lysosomal or proteosomal pathways [28,29,51,52].…”

“…Given that phosphorylation of Cx43 by PKCa has been previously reported to affect the protein conformation and its interaction with other intracellular proteins [6,22,[43][44][45], taken together all these data implied that TRPC1-mediated m-calpain/PKCa pathway was critically involved in Cx43 remodeling at the plasma membrane. Table 1 Boltzmann Parameters for gap Junctions in untreated and SCR-, GdCb-TRPCl-siRNA-treated C2C12 cell pairs stimulated or not with SIP…”

“…This assumption is consistent Note that the active pool of membrane associated-PKCa progressively decreases with myoblast differentiation both in unstimulated and S1P-stimulated cells and that the treatment with TRPC1-siRNA, m-calpain-siRNA and GdCl 3 prevents the reduction of active PKCa with previous observations in the literature showing that Ca 2? / PKCa -dependent phosphorylation of connexins [44] can influence their interaction with other proteins at the plasma membrane [22,45].…”

“…There is a substantial body of evidence showing that connexin (Cx)-containing gap junctions are involved in the coordination of numerous cell functions and differentiation processes during organogenesis, through the establishment of direct intercellular communications between neighboring cells [20][21][22]. Cx43 protein is the predominant connexin in skeletal muscle and its involvement in myogenesis and muscle regeneration have been well documented [6,[23][24][25].…”

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

“…36), although commercial antibodies were only found for Ser 368. Since we observed an B83% reduction in the total Cx43 protein levels in Tmem65 knockdown (KD) mNCM Fig.…”