Makarenkova Helen P, Shestopalov Valery I
Department of Cell and Molecular Biology, The Scripps Research Institute La Jolla, CA, USA.
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine Miami, FL, USA ; Department of Cell Biology and Anatomy, Vavilov Institute for General Genetics Moscow, Russia.
Front Physiol. 2014 Feb 25;5:63. doi: 10.3389/fphys.2014.00063. eCollection 2014.
Tissue injury involves coordinated systemic responses including inflammatory response, targeted cell migration, cell-cell communication, stem cell activation and proliferation, and tissue inflammation and regeneration. The inflammatory response is an important prerequisite for regeneration. Multiple studies suggest that extensive cell-cell communication during tissue regeneration is coordinated by purinergic signaling via extracellular adenosine triphosphate (ATP). Most recent data indicates that ATP release for such communication is mediated by hemichannels formed by connexins and pannexins. The Pannexin family consists of three vertebrate proteins (Panx 1, 2, and 3) that have low sequence homology with other gap junction proteins and were shown to form predominantly non-junctional plasma membrane hemichannels. Pannexin-1 (Panx1) channels function as an integral component of the P2X/P2Y purinergic signaling pathway and is arguably the major contributor to pathophysiological ATP release. Panx1 is expressed in many tissues, with highest levels detected in developing brain, retina and skeletal muscles. Panx1 channel expression and activity is reported to increase significantly following injury/inflammation and during regeneration and differentiation. Recent studies also report that pharmacological blockade of the Panx1 channel or genetic ablation of the Panx1 gene cause significant disruption of progenitor cell migration, proliferation, and tissue regeneration. These findings suggest that pannexins play important roles in activation of both post-injury inflammatory response and the subsequent process of tissue regeneration. Due to wide expression in multiple tissues and involvement in diverse signaling pathways, pannexins and connexins are currently being considered as therapeutic targets for traumatic brain or spinal cord injuries, ischemic stroke and cancer. The precise role of pannexins and connexins in the balance between tissue inflammation and regeneration needs to be further understood.
组织损伤涉及一系列协调的全身反应，包括炎症反应、靶向细胞迁移、细胞间通讯、干细胞激活与增殖以及组织炎症和再生。炎症反应是再生的重要前提。多项研究表明，组织再生过程中广泛的细胞间通讯是由细胞外三磷酸腺苷（ATP）介导的嘌呤能信号传导协调的。最新数据表明，这种通讯所需的ATP释放是由连接蛋白和泛连接蛋白形成的半通道介导的。泛连接蛋白家族由三种脊椎动物蛋白（Panx 1、2和3）组成，它们与其他间隙连接蛋白的序列同源性较低，并且主要形成非连接性的质膜半通道。泛连接蛋白-1（Panx1）通道是P2X/P2Y嘌呤能信号通路的一个组成部分，可以说是病理生理ATP释放的主要贡献者。Panx1在许多组织中表达，在发育中的大脑、视网膜和骨骼肌中检测到的水平最高。据报道，在损伤/炎症后以及再生和分化过程中，Panx1通道的表达和活性会显著增加。最近的研究还报告说，Panx1通道的药理学阻断或Panx1基因的基因敲除会导致祖细胞迁移、增殖和组织再生的显著破坏。这些发现表明，泛连接蛋白在损伤后炎症反应的激活以及随后的组织再生过程中发挥着重要作用。由于在多种组织中广泛表达并参与多种信号通路，泛连接蛋白和连接蛋白目前被视为创伤性脑损伤或脊髓损伤、缺血性中风和癌症的治疗靶点。泛连接蛋白和连接蛋白在组织炎症和再生平衡中的精确作用有待进一步了解。
