Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease

Abstract

Connexins are tetraspan transmembrane proteins that form gap junctions and facilitate direct intercellular communication, a critical feature for the development, function, and homeostasis of tissues and organs. In addition, a growing number of gap junction-independent functions are being ascribed to these proteins. The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional level, and undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability, and function. Here, we summarize these key regulatory events, with emphasis on how these affect connexin multifunctionality in health and disease.

Prevention of connexin-43 remodeling protects against Duchenne muscular dystrophy cardiomyopathy

“…However, we found no difference in the level of phosphorylated Cx43-S365 compared with total Cx43 between mdx and mdx:MM-VV heart lysates (Supplemental Figure 6). Cx43 can be phosphorylated at more than 20 different residues by different kinases, and at least 9 of the phosphorylated residues have been reported to be phosphorylated by 2 to 4 different kinases (14). We believe that a potential crosstalk between protein kinases may obscure some of their individual contributions.…”

“…Connexin-43 (Cx43) is the most abundant connexin protein in the ventricular myocardium (12). In the heart, Cx43 is a short-lived protein that undergoes numerous posttranslational modifications (PTMs), including phosphorylation of the intracellular carboxyl terminus (13,14). PTMs regulate many aspects of the Cx43 life cycle, notably the redistribution of Cx43 away from IDs and toward the lateral cardiomyocyte sarcolemma in a phenomenon termed gap junctional remodeling (14,15).…”

“…In the heart, Cx43 is a short-lived protein that undergoes numerous posttranslational modifications (PTMs), including phosphorylation of the intracellular carboxyl terminus (13,14). PTMs regulate many aspects of the Cx43 life cycle, notably the redistribution of Cx43 away from IDs and toward the lateral cardiomyocyte sarcolemma in a phenomenon termed gap junctional remodeling (14,15). At these lateral sites, Cx43 exists as unopposed hemichannels that can contribute to disruption of ionic gradient and loss of essential metabolites; indeed, hemichannels have been shown to contribute to cardio-Aberrant expression of the cardiac gap junction protein connexin-43 (Cx43) has been suggested as playing a role in the development of cardiac disease in the mdx mouse model of Duchenne muscular dystrophy (DMD); however, a mechanistic understanding of this association is lacking.…”

The Role of Gap Junction in Regulating Vascular Function and Its Relationship with Hypertension

“…GJ is currently found in membrane channels of many cells. GJ is the only kind of cell membrane channel which allows adjacent cells to directly exchange substances in the cytoplasm [5]. Electrical signals and ions or small molecules with a molecular mass below 1000 D or less than 1.0 nm in diameter, such as small molecule metabolites, water molecules, and second messengers (Ca 2+ , IP3, cAMP) were allowed to pass through GJ [6].…”

Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

“…Twenty-one human connexin proteins form the main structural units of gap junctions, which are intercellular channels that allow the direct diffusion of ions and small molecules between neighboring cells [ 1 ]. The critical importance of connexins and gap junctional intercellular communication (GJIC) in normal tissue physiology is evident from the multitude of human diseases associated with connexin mutations and the dysregulation of gap junctions observed in many pathological conditions [ 2 ].…”