Sigmar1's Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology

Overview

Journal Front Physiol

Date 2021 Jul 26

PMID 34305655

Citations 35

Authors

Richa Aishwarya

Chowdhury S Abdullah

Mahboob Morshed

Naznin Sultana Remex

Md Shenuarin Bhuiyan

Affiliations

Soon will be listed here.

Abstract

The Sigma 1 receptor (Sigmar1) is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein playing a diverse role in cellular survival. Recessive mutation in Sigmar1 have been identified as a causative gene for neuronal and neuromuscular disorder. Since the discovery over 40 years ago, Sigmar1 has been shown to contribute to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and involved in cellular survival. Alterations in Sigmar1's subcellular localization, expression, and signaling has been implicated in the progression of a wide range of diseases, such as neurodegenerative diseases, ischemic brain injury, cardiovascular diseases, diabetic retinopathy, cancer, and drug addiction. The goal of this review is to summarize the current knowledge of Sigmar1 biology focusing the recent discoveries on Sigmar1's molecular, cellular, pathophysiological, and biological functions.

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References

Su T, London E, Jaffe J . Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science. 1988; 240(4849):219-21. DOI: 10.1126/science.2832949. View

Hayashi T, Su T . The potential role of sigma-1 receptors in lipid transport and lipid raft reconstitution in the brain: implication for drug abuse. Life Sci. 2005; 77(14):1612-24. DOI: 10.1016/j.lfs.2005.05.009. View

Mitsuda T, Omi T, Tanimukai H, Sakagami Y, Tagami S, Okochi M . Sigma-1Rs are upregulated via PERK/eIF2α/ATF4 pathway and execute protective function in ER stress. Biochem Biophys Res Commun. 2011; 415(3):519-25. DOI: 10.1016/j.bbrc.2011.10.113. View

Laurini E, Col V, Mamolo M, Zampieri D, Posocco P, Fermeglia M . Homology Model and Docking-Based Virtual Screening for Ligands of the σ1 Receptor. ACS Med Chem Lett. 2014; 2(11):834-9. PMC: 4017991. DOI: 10.1021/ml2001505. View

Ullah M, Ahmad A, Raza S, Amar A, Ali A, Bhatti A . In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia. Neurogenetics. 2015; 16(4):299-306. DOI: 10.1007/s10048-015-0453-1. View

Kekuda R, Prasad P, Fei Y, Leibach F, Ganapathy V . Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1). Biochem Biophys Res Commun. 1996; 229(2):553-8. DOI: 10.1006/bbrc.1996.1842. View

Bernard-Marissal N, Medard J, Azzedine H, Chrast R . Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain. 2015; 138(Pt 4):875-90. DOI: 10.1093/brain/awv008. View

Maurice T, Volle J, Strehaiano M, Crouzier L, Pereira C, Kaloyanov N . Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer's disease by positive modulation of σ receptors. Pharmacol Res. 2019; 144:315-330. DOI: 10.1016/j.phrs.2019.04.026. View

Novakova M, Ela C, Barg J, Vogel Z, Hasin Y, Eilam Y . Inotropic action of sigma receptor ligands in isolated cardiac myocytes from adult rats. Eur J Pharmacol. 1995; 286(1):19-30. DOI: 10.1016/0014-2999(95)00424-j. View

10.

Gao X, Yao J, He Y, Hu C, Mei Y . Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. PLoS One. 2012; 7(11):e49384. PMC: 3489664. DOI: 10.1371/journal.pone.0049384. View

11.

Omori I, Watanabe N, Nakagawa A, Cipriani A, Barbui C, McGuire H . Fluvoxamine versus other anti-depressive agents for depression. Cochrane Database Syst Rev. 2010; (3):CD006114. PMC: 4171125. DOI: 10.1002/14651858.CD006114.pub2. View

12.

John C, Gulden M, Li J, Bowen W, McAfee J, Thakur M . Synthesis, in vitro binding, and tissue distribution of radioiodinated 2-[125I]N-(N-benzylpiperidin-4-yl)-2-iodo benzamide, 2-[125I]BP: a potential sigma receptor marker for human prostate tumors. Nucl Med Biol. 1998; 25(3):189-94. DOI: 10.1016/s0969-8051(97)00168-6. View

13.

Lenze E, Mattar C, Zorumski C, Stevens A, Schweiger J, Nicol G . Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020; 324(22):2292-2300. PMC: 7662481. DOI: 10.1001/jama.2020.22760. View

14.

Christ M, Huesmann H, Nagel H, Kern A, Behl C . Sigma-1 Receptor Activation Induces Autophagy and Increases Proteostasis Capacity In Vitro and In Vivo. Cells. 2019; 8(3). PMC: 6468724. DOI: 10.3390/cells8030211. View

15.

Kubickova J, Lencesova L, Csaderova L, Stracina T, Hudecova S, Babula P . Haloperidol Affects Plasticity of Differentiated NG-108 Cells Through σ1R/IPR1 Complex. Cell Mol Neurobiol. 2017; 38(1):181-194. PMC: 5775985. DOI: 10.1007/s10571-017-0524-y. View

16.

Sun Y, Sukumaran P, Singh B . Sigma1 Receptor Inhibits TRPC1-Mediated Ca Entry That Promotes Dopaminergic Cell Death. Cell Mol Neurobiol. 2020; 41(6):1245-1255. PMC: 11448707. DOI: 10.1007/s10571-020-00892-5. View

17.

Chien C, Pasternak G . Selective antagonism of opioid analgesia by a sigma system. J Pharmacol Exp Ther. 1994; 271(3):1583-90. View

18.

Senda T, Matsuno K, Kobayashi T, Mita S . Reduction of the scopolamine-induced impairment of passive-avoidance performance by sigma receptor agonist in mice. Physiol Behav. 1997; 61(2):257-64. DOI: 10.1016/s0031-9384(96)00447-7. View

19.

Azzariti A, Colabufo N, Berardi F, Porcelli L, Niso M, Simone G . Cyclohexylpiperazine derivative PB28, a sigma2 agonist and sigma1 antagonist receptor, inhibits cell growth, modulates P-glycoprotein, and synergizes with anthracyclines in breast cancer. Mol Cancer Ther. 2006; 5(7):1807-16. DOI: 10.1158/1535-7163.MCT-05-0402. View

20.

Abou-Lovergne A, Collado-Hilly M, Monnet F, Koukoui O, Prigent S, Coquil J . Investigation of the role of sigma1-receptors in inositol 1,4,5-trisphosphate dependent calcium signaling in hepatocytes. Cell Calcium. 2011; 50(1):62-72. DOI: 10.1016/j.ceca.2011.05.008. View