<br>IP3受体：从结构到信号的“基本”旅程,Cell Calcium

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IP3受体：从结构到信号的“基本”旅程
Cell Calcium ( IF 4.3 ) Pub Date : 2023-05-23 , DOI: 10.1016/j.ceca.2023.102761
Holly A Smith ₁ , Nagendra Babu Thillaiappan ₂ , Ana M Rossi ₁

Affiliation

肌醇 1,4,5-三磷酸受体 (IPR) 是大型四聚体通道，主要位于内质网 (ER) 膜中，并介导几乎所有细胞响应细胞外刺激而从细胞内储存释放 Ca2+。 IP 和 Ca 本身对 IPR 的双重调节、上游“许可”以及将 IPR 排列成内质网膜中的小簇，使 IPR 能够产生空间和时间上多样化的 Ca 信号。 IPR 受胞质 Ca 浓度的特征性双相调节通过 Ca 诱导的 Ca 释放来支持再生 Ca 信号，同时还防止不受控制的爆炸性 Ca 释放。通过这种方式，细胞可以利用简单的离子（例如 Ca）作为近乎通用的细胞内信使来调节多种细胞功能，包括那些具有相互冲突结果的细胞功能，例如细胞存活和细胞死亡。以不同组合与IP和Ca结合的IPR的高分辨率结构已经开始揭示这个巨大通道的运作方式。在这里，我们在最近发表的结构的背景下讨论IPR及其细胞地理的严格调控如何导致被称为Ca“泡芙”的“基本”局部Ca信号的产生，这形成了所有IP介导的基本瓶颈胞浆 Ca 信号必须首先通过。

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IP3 receptors: An “elementary” journey from structure to signals

Inositol 1,4,5-trisphosphate receptors (IPRs) are large tetrameric channels which sit mostly in the membrane of the endoplasmic reticulum (ER) and mediate Ca release from intracellular stores in response to extracellular stimuli in almost all cells. Dual regulation of IPRs by IP and Ca itself, upstream “licensing”, and the arrangement of IPRs into small clusters in the ER membrane, allow IPRs to generate spatially and temporally diverse Ca signals. The characteristic biphasic regulation of IPRs by cytosolic Ca concentration underpins regenerative Ca signals by Ca-induced Ca-release, while also preventing uncontrolled explosive Ca release. In this way, cells can harness a simple ion such as Ca as a near-universal intracellular messenger to regulate diverse cellular functions, including those with conflicting outcomes such as cell survival and cell death. High-resolution structures of the IPR bound to IP and Ca in different combinations have together started to unravel the workings of this giant channel. Here we discuss, in the context of recently published structures, how the tight regulation of IPRs and their cellular geography lead to generation of “elementary” local Ca signals known as Ca “puffs”, which form the fundamental bottleneck through which all IP-mediated cytosolic Ca signals must first pass.

更新日期：2023-05-23

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