<br>了解 IP3R 通道：从结构基础到配体依赖性构象景观,Cell Calcium

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了解 IP3R 通道：从结构基础到配体依赖性构象景观
Cell Calcium ( IF 4.3 ) Pub Date : 2023-06-22 , DOI: 10.1016/j.ceca.2023.102770
Mariah R Baker ₁ , Guizhen Fan ₁ , Vikas Arige ₂ , David I Yule ₂ , Irina I Serysheva ₁

Affiliation

肌醇 1,4,5-三磷酸受体（IPR）是普遍表达的大电导钙通透性通道，主要定位于几乎所有真核细胞类型的内质网（ER）膜。IPR 作为 Ca 信号转导枢纽，通过它处理不同的细胞外刺激和细胞内输入，然后整合以从 ER 腔递送 Ca，从而产生具有精确时间和空间特性的胞质 Ca 信号。IPR 介导的 Ca 信号控制着大量的细胞功能，从基因转录和分泌到更神秘的大脑活动，如学习和记忆。当 IPR 同时绑定 IP 和 Ca（主要通道激动剂）时，IPR 会打开并释放 Ca。尽管压倒性的证据支持 IP 和 Ca 在 IPR 的激活和抑制中的功能相互作用，但对 IPR 通道如何通过两种主要激动剂的相互作用传达其门控的机制理解仍然是该领域的主要难题之一。过去十年中，使用低温电子显微镜阐明配体结合、离子渗透、离子选择性和 IPR 通道门控的分子机制方面取得了很大进展。本综述总结了这些研究的结果，为 IPR 的结构和功能研究的未来提供了前瞻性的观点。

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Understanding IP3R channels: From structural underpinnings to ligand-dependent conformational landscape

Inositol 1,4,5-trisphosphate receptors (IPRs) are ubiquitously expressed large-conductance Ca-permeable channels predominantly localized to the endoplasmic reticulum (ER) membranes of virtually all eukaryotic cell types. IPRs work as Ca signaling hubs through which diverse extracellular stimuli and intracellular inputs are processed and then integrated to result in delivery of Ca from the ER lumen to generate cytosolic Ca signals with precise temporal and spatial properties. IPR-mediated Ca signals control a vast repertoire of cellular functions ranging from gene transcription and secretion to the more enigmatic brain activities such as learning and memory. IPRs open and release Ca when they bind both IP and Ca, the primary channel agonists. Despite overwhelming evidence supporting functional interplay between IP and Ca in activation and inhibition of IPRs, the mechanistic understanding of how IPR channels convey their gating through the interplay of two primary agonists remains one of the major puzzles in the field. The last decade has seen much progress in the use of cryogenic electron microscopy to elucidate the molecular mechanisms of ligand binding, ion permeation, ion selectivity and gating of the IPR channels. The results of these studies, summarized in this review, provide a prospective view of what the future holds in structural and functional research of IPRs.

更新日期：2023-06-22

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