Connexins in the Heart: Regulation, Function and Involvement in Cardiac Disease

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.

The Role of Connexin Hemichannels in Inflammatory Diseases

“…Cx43, as well as CxHC, forms gap junctions in the heart. Gap junctions are predominantly located in the intercalated discs between cardiac myocytes, and serve to facilitate the propagation of electrical excitation, whereas CxHC are mainly located in an area (termed perinexus) surrounding the intercalated discs [21,137]. Similar to the CNS, cardiac CxHC are also induced to open during ischemia/hypoxia [138,139].…”

“…Similar to the CNS, cardiac CxHC are also induced to open during ischemia/hypoxia [138,139]. The inhibition of CxHC with 43Gap26, GAP19 or Peptide5 reduces ischemia-induced heart damage [21,44,96,108,123,140]. In contrast to Cx43HC blockers, a PxHC blocker (i.e., 10Panx1) did not show any protection [44,123].…”

Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

“…Connexins are channel proteins that form hemichannels specialized in cell-to-cell communication at the intercalated disks [103]. Connexins enable the passive diffusion of compounds up to 1 kDa between two connected cells [104]. Depending on the connexin isoform, they transport water, ions, and second messengers, such as IP3, ADP, ATP, cAMP, and miRNAs [104].…”

“…Connexins enable the passive diffusion of compounds up to 1 kDa between two connected cells [104]. Depending on the connexin isoform, they transport water, ions, and second messengers, such as IP3, ADP, ATP, cAMP, and miRNAs [104]. Because of this role, connexins play a vital role in the heart by coordinating the depolarization of cardiac muscle and ensuring cardiac muscle function.…”

Molecular Imaging of Human Skeletal Myoblasts (huSKM) in Mouse Post-Infarction Myocardium

“…Previous reports have shown that myoblast therapy improves the functionality of the MI heart, affecting angiogenesis [ 9 , 10 ], inflammation [ 11 ], matrix remodelling, tissue cell reservoir proliferation (CPC-cardiac progenitor cells), or inhibition of cardiomyocytes apoptosis. Unfortunately, huSkM do not express connexin 43 (Cx43)–the principal element of functional gap junctions that is critical for cell-to-cell communications [ 12 ]. We [ 13 ] and others have previously shown that introducing the Cx43-overexpressing vectors led to the improvement of electrical coupling in vitro [ 14 , 15 ] and in vivo between neighbouring cardiomyocytes localised in the peri-infarction zone and the surrounding myocardium [ 16 ].…”