Leybaert Luc, Lampe Paul D, Dhein Stefan, Kwak Brenda R, Ferdinandy Peter, Beyer Eric C, Laird Dale W, Naus Christian C, Green Colin R, Schulz Rainer
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.)
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.).
Pharmacol Rev. 2017 Oct;69(4):396-478. doi: 10.1124/pr.115.012062.
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.
连接蛋白是普遍存在的形成通道的蛋白质，它们组装成质膜半通道以及直接连接细胞的细胞间缝隙连接通道。在心脏中，缝隙连接通道将心肌细胞和特殊传导组织电连接起来，以协调心房和心室的收缩/舒张周期及泵功能。在血管中，这些通道促进内皮细胞的远距离通讯，使平滑肌细胞收缩同步，并支持内皮细胞与平滑肌细胞的通讯。在中枢神经系统中，它们形成细胞合体并协调神经功能。缝隙连接通道通常是开放的，而半通道通常是关闭的，但病理状况可能会限制缝隙连接通讯并促进半通道开放，从而扰乱微妙的细胞通讯平衡。直到最近，大多数针对连接蛋白的药物特异性都很低，并且有几种脱靶效应。最近基于肽的研究方法已显示出更高的特异性，并为更合理地独立调节缝隙连接和半通道的功能开辟了道路。我们在此综述连接蛋白及其通道在心血管和神经血管健康与疾病中的作用，重点关注关键的调节方面以及识别可改变其功能的潜在靶点。我们得出结论，基于肽的研究为干扰连接蛋白及其通道带来了几个新机会，这可能很快就能实现保留缝隙连接通讯、抑制半通道开放以及减轻炎症信号传导。
