Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues

Abstract

Gap junctions, composed of proteins from the connexin family, allow for intercellular communication between cells in essentially all tissues. There are 21 connexin genes in the human genome and different tissues express different connexin genes. Most connexins are known to be phosphoproteins. Phosphorylation can regulate connexin assembly into gap junctions, gap junction turnover and channel gating. Given the importance of gap junctions in development, proliferation and carcinogenesis, regulation of gap junction phosphorylation in response to wounding, hypoxia and other tissue insults is proving to be critical for cellular response and return to homeostasis. Connexin43 (Cx43) is the most widely and highly expressed gap junction protein, both in cell culture models and in humans, thus more research has been done on it and more reagents to it are available. In particular, antibodies that can report Cx43 phosphorylation status have been created allowing temporal examination of specific phosphorylation events in vivo. This review is focused on the use of these antibodies in tissue in situ, predominantly looking at Cx43 phosphorylation in brain, heart, endothelium and epithelium with reference to other connexins where data is available. These data allow us to begin to correlate specific phosphorylation events with changes in cell and tissue function.

Coculture of Embryonic Ventricular Myocytes and Mouse Embryonic Stem Cell Enhance Intercellular Signaling by Upregulation of Connexin43

“…The total amount of pCx43 was increased in the CO group. Phosphorylation at different amino acid residues has different physiological effects: S368 phosphorylation by PKC is increased after ischemia [28], causing the disassembly of Cx43 in GJ plaques, inhibiting dye transfer and reduction of gap junctional intercellular communication [29,30]. Our results show that there is no difference in S368-phosphorylated Cx43 between the two groups.…”

Connexin 43 (Cx43) Expression in Laryngeal Squamous Cell Carcinomas: Preliminary Data on Its Possible Prognostic Role

“…Its channel function depends on phosphorylation and dephosphorylation of the C-terminal domain, but recent evidence suggests its potential role as scaffold protein promoting the different assembly of the actin cytoskeleton and microtubules [4,6]. It seems that the C-terminal domain of Cx43 is responsible either for the tumor suppressor effect or the invasiveness, regulating also the epithelial-mesenchymal transition [7]; therefore the presence of two different activities of Cx43 protein has been proposed, one involving intercellular communication across communicating hemichannels and one acting as scaffold for cytoskeleton associated proteins [4].…”

Internal Ribosomal Entry Site (IRES) Activity Generates Endogenous Carboxyl-terminal Domains of Cx43 and Is Responsive to Hypoxic Conditions

“…Among the cytoplasmic portions, the carboxyl-terminal cytosolic tail represents the most variable (in both length and composition) segment of connexins, whereas the aminoterminal domain, capable of self-assembly and hexamer formation, is conserved between members of the connexin family (2). The cytoplasmic C-tail of connexins has been found to be dispensable for channel formation, but it constitutes a site of multiple protein-protein interactions, including phosphorylation through PKA and PKC and anchoring through scaffolding proteins (3,4).…”