Life Science Institute, Zhejiang University, Hangzhou, 310058, Zhejiang, People's Republic of China.
Department of Biochemistry, University of Kashmir, Hazratbal, Jammu and Kashmir, India.
Mol Cell Biochem. 2021 Mar;476(3):1529-1540. doi: 10.1007/s11010-020-04002-3. Epub 2021 Jan 4.
Pannexins, large non-gap junction super family exists in vertebrates, play multiple roles in different cellular functions through their ATP release. Panx1-mediated adenosine 5'-triphosphate (ATP) release plays a vital role in physiological and pathophysiological conditions and is known major extracellular molecule in purinergic signaling. To modulate their function in vivo, a proper regulation of channel is necessary. Post-translational modifications are considered to be some regulating mechanisms for PANX1, while PANX2, PANX3 have been uncharacterized to date. Through their significant evidences, PANXs exclude from gap junction and conduits ATP release and other cellular molecules from cells by various mechanisms. PANX1 is most extensive characterized and implicated in ATP signaling and inflammatory processes. Despite the constant advances, much significance of PANX1 in physiological processes remains elusive. Recently, various research groups along with our group have reported the Cryo-EM structure of Panx1 channel and uncovered the hidden functions in structure-function mechanism as well as to provide the clear understanding in physiological and pathophysiological roles. These research groups reported the novel heptameric structure with contains 4 transmembrane helices (TM), two extracellular loops and one intracellular loop with N and C terminus located at the intracellular side. In addition, the structure contains a large pore of which an inhibitor CBX act as a plug that blocking the passage of substrate. In this context, this review will present current mechanistic understanding in structure and function together with significant physiological roles particularly ATP release in health and disease. As such, this review emphasizes on recent functional properties associated with novel heptameric channel and demystifies channel-mediated ATP release function.
质膜连接蛋白（Pannexins）是广泛存在于脊椎动物中的大型非间隙连接超级家族，通过释放 ATP 发挥多种细胞功能。Pannex1 介导的三磷酸腺苷（ATP）释放在生理和病理生理条件下发挥着重要作用，是嘌呤能信号传递的主要细胞外分子。为了在体内调节其功能，需要对通道进行适当的调节。翻译后修饰被认为是 Pannexin1 的一些调节机制，而 Pannexin2、Pannexin3 迄今为止尚未被描述。通过它们的重要证据，Pannexins 通过各种机制将缝隙连接和导管 ATP 释放以及其他细胞分子排除在细胞之外。Pannex1 是研究最广泛、与 ATP 信号转导和炎症过程关系最密切的蛋白。尽管不断取得进展，但 Pannexin1 在生理过程中的许多意义仍然难以捉摸。最近，许多研究小组与我们的小组一起报告了 Panx1 通道的冷冻电镜结构，并揭示了结构-功能机制中的隐藏功能，以及对生理和病理生理作用的清晰理解。这些研究小组报告了一种新型的七聚体结构，包含 4 个跨膜螺旋（TM）、两个细胞外环和一个细胞内环，N 端和 C 端位于细胞内。此外，该结构包含一个大孔，其中抑制剂 CBX 充当塞子，阻止底物通过。在这种情况下，本综述将介绍目前在结构和功能方面的机械理解，以及特别是在健康和疾病中与 ATP 释放相关的重要生理作用。因此，本综述强调了与新型七聚体通道相关的最近功能特性，并揭示了通道介导的 ATP 释放功能。
