Knocking Out Sigma-1 Receptors Reveals Diverse Health Problems

Abstract

Sigma-1 receptor (Sig-1R) is a protein present in several organs such as brain, lung, and heart. In a cell, Sig-1R is mainly located across the membranes of the endoplasmic reticulum and more specifically at the mitochondria-associated membranes. Despite numerous studies showing that Sig-1R could be targeted to rescue several cellular mechanisms in different pathological conditions, less is known about its fundamental relevance. In this review, we report results from various studies and focus on the importance of Sig-1R in physiological conditions by comparing Sig-1R KO mice to wild-type mice in order to investigate the fundamental functions of Sig-1R. We note that the Sig-1R deletion induces cognitive, psychiatric, and motor dysfunctions, but also alters metabolism of heart. Finally, taken together, observations from different experiments demonstrate that those dysfunctions are correlated to poor regulation of ER and mitochondria metabolism altered by stress, which could occur with aging.

Keywords: Endoplasmic reticulum; Mitochondria; Neurodegenerative disorders; Sigma-1 receptor.

Fig. 1

Sig-1R expression profile in different brain cell types in mice. Sigmar1 mRNA level in different brain cell populations in mice. Glial cells have a higher expression of Sig-1R than neurons. FPKM: Fragments per kilo base of exon per million reads mapped. Result extracted from brainrnaseq database (Zhang et al. 2014)

Fig. 2

Schematic summary of defects induced by the absence of Sig-1R in mice. AP action potential, BDNF brain-derived neurotrophic factor, ER endoplasmic reticulum, HPA axis hypothalamic–pituitary–adrenal axis

Fig. 3

Fundamental functions of Sig-1R on ER stress regulation. 1: Misfolded proteins increasing with age induce ER stress and modification in calcium homeostasis; 2: Calcium depletion in ER activates Sig-1R, which separates from BiP. Pathway a: IP3R and ATP production. 3a: Sig-1R interacts with IP3R and allows ankyrin to be detached from IP3R, which stabilize and enhance opening of IP3R. 4a: Calcium ions efflux from ER lumen into mitochondria through IP3R, VDAC, and MCU. 5a: Calcium ions increase in mitochondria enhances ATP production through TCA cycle and oxidative phosphorylation. Pathway b: Unfolded Protein Response. 3b: Sig-1R interacts with IRE1. 4b: Activated IRE1 acts as an endonuclease and is able to cut an intron from xbp1 to allow its translation. 5b: XBP1 allows the transcription of ER chaperone genes and pro-survival genes. ATP: adenosine triphosphate; BiP: binding immunoglobulin protein; ER: endoplasmic reticulum; ERAD: endoplasmic-reticulum-associated protein degradation; IP3R: inositol trisphosphate receptor; IRE1: inositol-requiring enzyme 1; MCU: mitochondrial calcium uniporter; OxPhos: oxidative phosphorylation; TCA: tricarboxylic acid cycle; VDAC: voltage-dependent anion channel; XBP1: X-box binding protein 1; xbp1s: xbp1 mRNA spliced; xbp1u: xbp1 mRNA unspliced