Abstract
Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Gap junctional channels put into contact the cytoplasms of connected cardiomyocytes, allowing the existence of electrical coupling. However, in addition to this fundamental role, connexins are also involved in cardiomyocyte death and survival. Thus, chemical coupling through gap junctions plays a key role in the spreading of injury between connected cells. Moreover, in addition to their involvement in cell-to-cell communication, mounting evidence indicates that connexins have additional gap junction-independent functions. Opening of unopposed hemichannels, located at the lateral surface of cardiomyocytes, may compromise cell homeostasis and may be involved in ischemia/reperfusion injury. In addition, connexins located at non-canonical cell structures, including mitochondria and the nucleus, have been demonstrated to be involved in cardioprotection and in regulation of cell growth and differentiation. In this review, we will provide, first, an overview on connexin biology, including their synthesis and degradation, their regulation and their interactions. Then, we will conduct an in-depth examination of the role of connexins in cardiac pathophysiology, including new findings regarding their involvement in myocardial ischemia/reperfusion injury, cardiac fibrosis, gene transcription or signaling regulation.
Highlights
Connexins are a large family of highly homologous transmembrane proteins, comprising 20 and 21 different isoforms in mice and humans, respectively [1,2,3]
Previous studies have demonstrated that the Connexin 43 (Cx43) CT domain interacts directly with microtubules [227], in a process that is inhibited by phosphorylation at Tyr247, a site known to be targeted by the tyrosine kinase Src [8,228]
GJIC is involved in chemical coupling, which allows the transfer of cytosolic signals between connected cells, and may be important in propagation of ischemia/reperfusion injury during myocardial infarction
Summary
Connexins are a large family of highly homologous transmembrane proteins, comprising 20 and 21 different isoforms in mice and humans, respectively [1,2,3]. Eps at the plasma membrane, followed by recruitment of clathrin, the GTPase dynamin, the clathrin adaptors AP-2 and DAB2 and the protein p62, which together target ubiquitinated Cx43 to the endocytic pathway [50,59,60] This process ends with the formation of a double-membrane structure, termed annular gap junction or connexosome, containing connexins from both cells [49,50,61,62]. Interruption of macroautophagy has been shown to result in retention of Cx43 at the plasma membrane, an effect associated with enhanced gap junction-mediated intercellular dye diffusion [60] In this process, p62 drives the annular gap junction to a forming autophagosome that would, fuse with a lysosome to degrade connexins [50]. Akt phosphorylation of Cx43 would promote stabilization of gap junctions, whereas Akt ubiquitination would remove this stabilizing factor [65]
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