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

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.

Keywords: Sigmar1; biological function; cellular function; molecular structure; physiological function.

FIGURE 1

Molecular characterization of Sigmar1. (A) Schematic diagram representing the genetic structure of the SIGMAR1 gene, including the exon and, intron lengths in terms of nucleotides and amino acids. (B) Simplified schematic of full-length Sigmar1 topology showing the first predicted one transmembrane (TM) structure with a TM domain-containing amino acid (aa) residues from 92 to 112, MPWAVGRR as the ER retention site, and regions important for ligand binding (exon 3 and Ser99-Leu106). (C) Simplified schematic of the full-length Sigmar1 topology showing the second predicted two TM structures with two TM domains (TM1 containing aa residues 11 to 31 and TM2 containing 81 to 101) and an extracellular loop (containing 50aa). Both N- and C- terminal of the protein are on the same side. (D) Simplified schematic for the recent crystal structure of full-length Sigmar1 suggesting the trimeric structure of the protein with trimerization of three single transmembrane domains and each transmembrane domain being tightly associated with one promoter. The C-terminal is located on the cytosolic side. (E) Schematic diagram representing full protein structure of Sigmar1 with structural details for receptor dimerization, ligand binding, cholesterol-, cocaine-, progesterone- binding.

FIGURE 2

Subcellular localization of Sigmar1. Cartoon showing a summary of the sub-cellular localization of Sigmar1 as evidenced by several studies using various cell types. Overall, the presence of Sigmar1 has been detected on the mitochondria-associated ER membrane (MAM), plasma membrane, ER membrane, nuclear membrane, mitochondria-associated ER membrane, mitochondrial membrane, nucleoplasmic reticulum and sub-surface cisternae in different cell types including CHO cells, human B and T cells, photoreceptor cells, and neuronal cell lines including NSC34 cells and neuro2a cells.

FIGURE 3

Localization of neuropathy-related mutations in the SIGMAR1 gene. Schematic diagram representing the genetic structure of the SIGMAR1 gene showing the locations of all the mutations related to skeletal muscle pathology.

FIGURE 4

Summary of the pathophysiological functions of Sigmar1. Schematic showing an overall summary of the role of Sigmar1 in the pathophysiology related to different organs as present in the current literature. Briefly, agonist-mediated activation of Sigmar1 has protective effects in pathological conditions of several organs including heart (cardiac hypertrophy, myocardial infarction, atrial fibrillation, vascular disease, drug-induced cardiomyopathy and maladaptive ER stress), brain (neurodegenerative diseases including AD, HD and PD (with the exception of MPTP-induced PD) and ischemic brain injuries), kidneys, retina, liver, and the immune system. Inhibition of Sigmar1 using its antagonists is reported to be protective in several pathologies including cancer, cocaine addiction, and COVID-19. However, due to conflicting reports on whether activation or inhibition of Sigmar1 is protective, the field remains inconclusive about the effects of Sigmar1 on methamphetamine and alcohol addiction.

FIGURE 5

Biological functions of Sigmar1. Schematic diagram summarizing the functions of Sigmar1 including its involvement in cognition, memory, ER stress, mitochondrial dynamics, mitochondrial respiration and function, autophagy, lipid transport from ER, and ion channel regulation.