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.

中文翻译：

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连接蛋白在心血管和神经血管健康和疾病中的药理学意义

连接蛋白是普遍存在的通道形成蛋白，可组装为质膜半通道和直接连接细胞的细胞间间隙连接通道。在心脏中，间隙连接通道电连接心肌细胞和专门的传导组织，以协调心房和心室收缩/舒张周期和泵功能。在血管中，这些通道促进长距离内皮细胞通讯，同步平滑肌细胞收缩，并支持内皮-平滑肌细胞通讯。在中枢神经系统中，它们形成细胞合胞体并协调神经功能。间隙连接通道通常是打开的，半通道通常是关闭的，但病理条件可能会限制间隙连接通讯并促进半通道打开，从而扰乱微妙的细胞通讯平衡。直到最近，大多数连接蛋白靶向药物都表现出很少的特异性和一些脱靶效应。最近基于肽的方法的工作已经证明了特异性的提高，并为独立调节间隙连接和半通道功能的更合理的方法开辟了途径。我们在这里回顾连接蛋白及其通道在心血管和神经血管健康和疾病中的作用，重点关注关键的调控方面和确定改变其功能的潜在靶点。我们的结论是，基于肽的研究为干扰连接蛋白及其通道提供了一些新的机会，这些机会可能很快就能保留间隙连接通讯、抑制半通道开放和减轻炎症信号传导。