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没有 TRPC 蛋白参与 SOCE、ROCE 和 CRAC 通道功能的遗传证据。

Genetic evidence against involvement of TRPC proteins in SOCE, ROCE, and CRAC channel function.

机构信息

Institute of Biomedical Research, School of Biomedical Sciences, Catholic University of Argentina, Buenos Aires C1107AFF, Argentina.

Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.

出版信息

Proc Natl Acad Sci U S A. 2024 Dec 3;121(49):e2411389121. doi: 10.1073/pnas.2411389121. Epub 2024 Nov 27.

DOI:10.1073/pnas.2411389121
PMID:39602257
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11626178/
Abstract

Using genetically engineered mice and cell lines derived from genetically engineered mice we show that depletion of ER delimited Ca stores activates heteromeric Ca entry (SOCE) channels formed obligatorily, but not exclusively by Orai1 molecules. Comparison of Orai-dependent Ca entries revealed Orai1 to be dominant when compared to Orai2 and Orai3. Unexpectedly, we found that store-depletion-activated Ca entry does not depend obligatorily on functionally intact TRPC molecules, as SOCE monitored with the Fura2 Ca reporter dye is unaffected in cells in which all seven TRPC coding genes have been structurally and functionally inactivated. Unexpectedly as well, we found that TRPC-independent Gq-coupled receptor-operated Ca entry (ROCE) also depends on Orai1. Biophysical measurements of Ca release activated Ca currents (Icrac) are likewise unaffected by ablation of all seven TRPC genes. We refer to mice and cells carrying the seven-fold disruption of TRPC genes as TRPC heptaKO mice and cells. TRPC heptaKO mice are fertile allowing the creation of a new homozygous inbred strain.

摘要

利用基因工程小鼠和源自基因工程小鼠的细胞系，我们证明了内质网限定的钙库耗竭会激活必需但并非排他性地由 Orai1 分子组成的异源钙内流（SOCE）通道。对 Orai 依赖性钙内流的比较表明，与 Orai2 和 Orai3 相比，Orai1 占主导地位。出乎意料的是，我们发现，钙库耗竭激活的钙内流并不必需依赖于功能完整的 TRPC 分子，因为用 Fura2 Ca 报告染料监测的 SOCE 在所有七个 TRPC 编码基因均已在结构和功能上失活的细胞中不受影响。同样出乎意料的是，我们发现，TRPC 非依赖性 Gq 偶联受体操纵的钙内流（ROCE）也依赖于 Orai1。钙释放激活钙电流（Icrac）的生物物理测量同样不受七个 TRPC 基因缺失的影响。我们将携带七个 TRPC 基因缺失的小鼠和细胞称为 TRPC 七缺失型小鼠和细胞。TRPC 七缺失型小鼠具有繁殖能力，可创建新的纯合近交系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/0a2b1f176699/pnas.2411389121fig12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/1949735f20e6/pnas.2411389121fig01.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/590af8fdff8c/pnas.2411389121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/6e48cbc6b39e/pnas.2411389121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/97a8631fff84/pnas.2411389121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/0431b1942b72/pnas.2411389121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/c075efeb1bf6/pnas.2411389121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/242e5ce22dc4/pnas.2411389121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/53b9d446bbe0/pnas.2411389121fig09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/9f4979806b3e/pnas.2411389121fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/37fee626890a/pnas.2411389121fig11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/0a2b1f176699/pnas.2411389121fig12.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/1949735f20e6/pnas.2411389121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/e143d26631bd/pnas.2411389121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/590af8fdff8c/pnas.2411389121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/6e48cbc6b39e/pnas.2411389121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/97a8631fff84/pnas.2411389121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/0431b1942b72/pnas.2411389121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/c075efeb1bf6/pnas.2411389121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/242e5ce22dc4/pnas.2411389121fig08.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/53b9d446bbe0/pnas.2411389121fig09.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/9f4979806b3e/pnas.2411389121fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/37fee626890a/pnas.2411389121fig11.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1694/11626178/0a2b1f176699/pnas.2411389121fig12.jpg

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本文引用的文献

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Cavβ1 regulates T cell expansion and apoptosis independently of voltage-gated Ca channel function.Cavβ1 通过独立于电压门控钙通道功能调节 T 细胞的增殖和凋亡。
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Angiotensin-II-Evoked Ca Entry in Murine Cardiac Fibroblasts Does Not Depend on TRPC Channels.血管紧张素 II 诱导的小鼠心肌成纤维细胞钙内流不依赖于 TRPC 通道。
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Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia/reoxygenation injuries.
3/6/7 类 TRPC 通道对心肌缺血/再灌注和细胞缺氧/复氧损伤的主要贡献。
Proc Natl Acad Sci U S A. 2017 Jun 6;114(23):E4582-E4591. doi: 10.1073/pnas.1621384114. Epub 2017 May 19.
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Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol.二酰基甘油对通道门控作用需要NHERF与TRPC4/5蛋白进行动态相互作用。
Proc Natl Acad Sci U S A. 2017 Jan 3;114(1):E37-E46. doi: 10.1073/pnas.1612263114. Epub 2016 Dec 19.
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The TRPC family of TRP channels: roles inferred (mostly) from knockout mice and relationship to ORAI proteins.瞬时受体电位通道（TRP）家族中的TRPC通道：（大多）从基因敲除小鼠推断出的作用及其与ORAI蛋白的关系
Handb Exp Pharmacol. 2014;223:1055-75. doi: 10.1007/978-3-319-05161-1_14.
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PLC-mediated PI(4,5)P2 hydrolysis regulates activation and inactivation of TRPC6/7 channels.PLC 介导热激蛋白 4,5-二磷酸酯水解调节 TRPC6/7 通道的激活和失活。
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Characterization of selective Calcium-Release Activated Calcium channel blockers in mast cells and T-cells from human, rat, mouse and guinea-pig preparations.鉴定人、鼠、豚鼠和大、小鼠肥大细胞和 T 细胞中的选择性钙释放激活钙通道阻滞剂。
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Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms.规范瞬时受体通道 5（TRPC5）和 TRPC1/4 通过不同的细胞机制导致癫痫发作和兴奋性毒性。
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TRPC1 proteins confer PKC and phosphoinositol activation on native heteromeric TRPC1/C5 channels in vascular smooth muscle: comparative study of wild-type and TRPC1-/- mice.TRPC1 蛋白使血管平滑肌中原位异源型 TRPC1/C5 通道的 PKC 和磷酸肌醇激活：野生型和 TRPC1-/- 小鼠的比较研究。
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