The Sigma-1 Receptor in Cellular Stress Signaling.

Teruo Hayashi

doi:10.3389/fnins.2019.00733

Abstract

After decades of research, the sigma-1 receptor (Sig-1R)’s structure, and molecular functions are being unveiled. Sig-1R is an integral endoplasmic reticulum (ER) membrane protein which forms an oligomer and binds a variety of psychotropic drugs. It forms a complex with the ER chaperone BiP that controls specific signaling molecules’ stability and function at the ER to regulate Ca2+ signaling, bioenergetics, and ER stress. Sig-1R is highly enriched in ER subdomains that are physically linked to outer mitochondrial membranes, reflecting its role in regulating ER–mitochondria communications. Thus, Sig-1R ligands are expected to serve as novel neuroprotective agents which treat certain psychiatric and neurodegenerative disorders. In this short review, the cell biological aspects of Sig-1R are discussed, with a particular focus on its role in fundamental ER functions.

Highlights

The sigma receptor was originally proposed to be a subtype of the G protein-coupled opioid receptors (Su and Hayashi, 2003)
sigma-1 receptor (Sig-1R) acts as a suppressor of endoplasmic reticulum (ER) stress-induced neuronal damage both in vitro and in vivo
Sig-1R has been shown to co-localize with Kv2.1 potassium channels on specialized ER membranes in spinal cord neurons (Mavlyutov et al, 2010, 2013)

Summary

Teruo Hayashi*

Reviewed by: Arnold Eino Ruoho, University of Wisconsin School of Medicine and Public Health, United States Kenji Hashimoto, Chiba University, Japan. Sig-1R is an integral endoplasmic reticulum (ER) membrane protein which forms an oligomer and binds a variety of psychotropic drugs. It forms a complex with the ER chaperone BiP that controls specific signaling molecules’ stability and function at the ER to regulate Ca2+ signaling, bioenergetics, and ER stress. Sig-1R ligands are expected to serve as novel neuroprotective agents which treat certain psychiatric and neurodegenerative disorders. In this short review, the cell biological aspects of Sig-1R are discussed, with a particular focus on its role in fundamental ER functions

INTRODUCTION

Protein Synthesis and Trafficking

Lipid Synthesis

CONCLUSION