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Pharmacol Rev. 2017 Oct;69(4):396-478. doi: 10.1124/pr.115.012062.

Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications.

Author information

1
Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium (L.L.); Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington (P.D.L.); Institute for Pharmacology, University of Leipzig, Leipzig, Germany (S.D.); Department of Pathology and Immunology, Department of Medical Specialization-Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Department of Pediatrics, University of Chicago, Chicago, Illinois (E.C.B.); Department of Anatomy and Cell Biology, University of Western Ontario, Dental Science Building, London, Ontario, Canada (D.W.L.); Cellular and Physiological Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada (C.C.N.); Department of Ophthalmology and The New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (C.R.G.); and Physiologisches Institut, Justus-Liebig-Universität Giessen, Giessen, Germany (R.S.) Luc.Leybaert@UGent.be.
2
Physiology Group, Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium (L.L.); Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, Washington (P.D.L.); Institute for Pharmacology, University of Leipzig, Leipzig, Germany (S.D.); Department of Pathology and Immunology, Department of Medical Specialization-Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.); Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.); Pharmahungary Group, Szeged, Hungary (P.F.); Department of Pediatrics, University of Chicago, Chicago, Illinois (E.C.B.); Department of Anatomy and Cell Biology, University of Western Ontario, Dental Science Building, London, Ontario, Canada (D.W.L.); Cellular and Physiological Sciences, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada (C.C.N.); Department of Ophthalmology and The New Zealand National Eye Centre, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand (C.R.G.); and Physiologisches Institut, Justus-Liebig-Universität Giessen, Giessen, Germany (R.S.).

Abstract

Connexins are ubiquitous channel forming proteins that assemble as plasma membrane hemichannels and as intercellular gap junction channels that directly connect cells. In the heart, gap junction channels electrically connect myocytes and specialized conductive tissues to coordinate the atrial and ventricular contraction/relaxation cycles and pump function. In blood vessels, these channels facilitate long-distance endothelial cell communication, synchronize smooth muscle cell contraction, and support endothelial-smooth muscle cell communication. In the central nervous system they form cellular syncytia and coordinate neural function. Gap junction channels are normally open and hemichannels are normally closed, but pathologic conditions may restrict gap junction communication and promote hemichannel opening, thereby disturbing a delicate cellular communication balance. Until recently, most connexin-targeting agents exhibited little specificity and several off-target effects. Recent work with peptide-based approaches has demonstrated improved specificity and opened avenues for a more rational approach toward independently modulating the function of gap junctions and hemichannels. We here review the role of connexins and their channels in cardiovascular and neurovascular health and disease, focusing on crucial regulatory aspects and identification of potential targets to modify their function. We conclude that peptide-based investigations have raised several new opportunities for interfering with connexins and their channels that may soon allow preservation of gap junction communication, inhibition of hemichannel opening, and mitigation of inflammatory signaling.

PMID:
28931622
PMCID:
PMC5612248
DOI:
10.1124/pr.115.012062
[Indexed for MEDLINE]
Free PMC Article

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