Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Prilenia Therapeutics Development LTD, Herzliya 4673304, Israel.
Int J Mol Sci. 2021 Apr 15;22(8):4082. doi: 10.3390/ijms22084082.
The sigma-1 receptor (S1R) is a 223 amino acid-long transmembrane endoplasmic reticulum (ER) protein. The S1R modulates the activity of multiple effector proteins, but its signaling functions are poorly understood. S1R is associated with cholesterol, and in our recent studies we demonstrated that S1R association with cholesterol induces the formation of S1R clusters. We propose that these S1R-cholesterol interactions enable the formation of cholesterol-enriched microdomains in the ER membrane. We hypothesize that a number of secreted and signaling proteins are recruited and retained in these microdomains. This hypothesis is consistent with the results of an unbiased screen for S1R-interacting partners, which we performed using the engineered ascorbate peroxidase 2 (APEX2) technology. We further propose that S1R agonists enable the disassembly of these cholesterol-enriched microdomains and the release of accumulated proteins such as ion channels, signaling receptors, and trophic factors from the ER. This hypothesis may explain the pleotropic signaling functions of the S1R, consistent with previously observed effects of S1R agonists in various experimental systems.
sigma-1 受体（S1R）是一种 223 个氨基酸长的跨膜内质网（ER）蛋白。S1R 调节多种效应蛋白的活性，但它的信号功能知之甚少。S1R 与胆固醇有关，在我们最近的研究中，我们证明了 S1R 与胆固醇的结合诱导了 S1R 簇的形成。我们提出，这些 S1R-胆固醇相互作用使 ER 膜中的富含胆固醇的微区得以形成。我们假设许多分泌蛋白和信号蛋白被招募并保留在这些微区中。这一假设与我们使用工程化的抗坏血酸过氧化物酶 2（APEX2）技术进行的 S1R 相互作用伙伴的无偏筛选结果一致。我们进一步提出，S1R 激动剂能够使这些富含胆固醇的微区解体，并从 ER 释放积累的蛋白质，如离子通道、信号受体和营养因子。这一假设可以解释 S1R 的多效性信号功能，与先前在各种实验系统中观察到的 S1R 激动剂的作用一致。
