The role of sigma 1 receptor in organization of endoplasmic reticulum signaling microdomains

Abstract

Sigma 1 receptor (S1R) is a 223-amino-acid-long transmembrane endoplasmic reticulum (ER) protein. S1R modulates activity of multiple effector proteins and is a well-established drug target. However, signaling functions of S1R in cells are poorly understood. Here, we test the hypothesis that biological activity of S1R in cells can be explained by its ability to interact with cholesterol and to form cholesterol-enriched microdomains in the ER membrane. By performing experiments in reduced reconstitution systems, we demonstrate direct effects of cholesterol on S1R clustering. We identify a novel cholesterol-binding motif in the transmembrane region of human S1R. Mutations of this motif impair association of recombinant S1R with cholesterol beads, affect S1R clustering in vitro and disrupt S1R subcellular localization. We demonstrate that S1R-induced membrane microdomains have increased local membrane thickness and that increased local cholesterol concentration and/or membrane thickness in these microdomains can modulate signaling of inositol-requiring enzyme 1α in the ER. Further, S1R agonists cause disruption of S1R clusters, suggesting that biological activity of S1R agonists is linked to remodeling of ER membrane microdomains. Our results provide novel insights into S1R-mediated signaling mechanisms in cells.

Neuroprotective Effects of Sigma 1 Receptor Ligands on Motoneuron Death after Spinal Root Injury in Mice

“…Similarly, in cardiomyocytes, the overexpression of Sig-1R under ER stress enhanced IRE1/XBP1s axis and reduced CHOP levels, preventing cell death [29]. Alternatively, under stress conditions such as neural injuries, Sig-1R could form cholesterol-enriched microdomains in the ER as proposed recently in vitro [47]. These changes in the ER membrane may modulate recruitment of ER proteins, such as IRE1, by forming big clusters enriched with Sig-1R and IRE1.…”

Sigma-1 Receptor Is Critical for Mitochondrial Activity and Unfolded Protein Response in Larval Zebrafish

“…Nevertheless, other groups have suggested a one transmembrane domain with a N-ter luminal and C-ter cytoplasmic localization [42]. Mavlyutov et al [43] and Zhemkov et al [9] proposed a one transmembrane domain with a N-ter cytosolic and C-ter luminal localization. As of today, no consensus topology of the protein has been clearly established.…”

“…In physiological conditions, its primary function is to act as a signal modulator that chaperones different partner proteins including inositol 1,4,5-trisphosphate receptor (IP3R), glucose-regulated protein (GRP-78; BiP), or inositol-requiring enzyme 1 (IRE1), among others [1,[3][4][5], leading to a modulation of several cellular responses and signaling pathways [6]. In cellular stress conditions, S1R dissociates from BiP, modulates cellular Ca 2+ homeostasis from ER to mitochondria through different mechanisms, impacting a variety of intracellular signal transduction systems [7][8][9]. Interestingly, S1R is expressed in different tissues such as the central nervous system (hippocampus, frontal cortex and olfactory bulb), heart, lungs, and kidneys, as well as endocrine, immune and reproductive tissues [10][11][12].…”

Selective Advantages of Synapses in Evolution

“…Specialized lipid chaperons can control Ca-dependent regulations and dynamic composition of lipid rafts at MCS [e.g., Sigma 1 receptor (Zhemkov et al, 2021a )], also acting as hubs of inter-organelle communications and signaling (Zhemkov et al, 2021c ). Not surprisingly that such regulations at MCS and mitochondria do control neuropeptide asymmetric distribution and secretion (Valadas et al, 2018 ; Zhao et al, 2018 ), cell death (Prudent et al, 2015 ) and contribute to mechanisms underlying neurological disorders (Schon and Area-Gomez, 2013 ; Zhemkov et al, 2021b ) and synaptopathies (Di Miceli et al, 2020 ).…”