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.
Highlights
Since the cloning of the first connexins in the 1980s, steady progress towards elucidating their regulation and function as signaling hubs and mediators of direct intercellular communication has been made [1,2,3]
Similar results have been found for other connexin mimetic peptides targeting the connexin 43 (Cx43) C-terminus (e.g., antiarrhythmic peptide 10 (AAP10) and rotigaptide (ZP123)), causing increases in Cx43-Ser368 phosphorylation through PKCα associated with improved cardiac functions in experimental animal models and early tests demonstrating no adverse effects in humans [192,218,219,220,221,222]
In order to fully understand the complex role of connexins in health and disease, it is essential to elucidate their regulation at all steps, from gene transcription, protein synthesis, post-translational modifications, and trafficking to their regulation at the cell membrane
Summary
Since the cloning of the first connexins in the 1980s, steady progress towards elucidating their regulation and function as signaling hubs and mediators of direct intercellular communication has been made [1,2,3]. The complexity and isoform-specificity of the connexin gene family is reflected by their links to numerous human diseases, many of which are rare syndromes with unique genotype–phenotype associations [6,7]. This latter phenomenon is underscored by the observation that mutations in different connexins can cause the same disease, whereas varying mutations in one connexin gene can result in vastly divergent diseases and phenotypes. This review aims to summarize and underscore important and unique mechanisms that regulate connexin function in healthy and diseased states, which shed light on clinical observations and future therapeutic opportunities. 2018r,e1v9ie,w12a9im6s to summarize and underscore important and unique mechanisms that regulate connexin function in healthy and diseased states, which shed light on clinical observations and future therapeutic opportunities Sci. 2018r,e1v9ie,w12a9im6s to summarize and underscore important and unique mechanisms that regulate connexin function in healthy and diseased states, which shed light on clinical observations and future therapeutic opportunities
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