The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer

Abstract

The sigma-1 receptor (σ1R) is an endoplasmic reticulum (ER)-resident chaperone protein that acts like an inter-organelle signaling modulator. Among its several functions such as ER lipid metabolisms/transports and indirect regulation of genes transcription, one of its most intriguing feature is the ability to regulate the function and trafficking of a variety of functional proteins. To date, and directly relevant to the present review, σ1R has been found to regulate both voltage-gated ion channels (VGICs) belonging to distinct superfamilies (i.e., sodium, Na+; potassium, K+; and calcium, Ca2+ channels) and non-voltage-gated ion channels. This regulatory function endows σ1R with a powerful capability to fine tune cells’ electrical activity and calcium homeostasis—a regulatory power that appears to favor cell survival in pathological contexts such as stroke or neurodegenerative diseases. In this review, we present the current state of knowledge on σ1R’s role in the regulation of cellular electrical activity, and how this seemingly adaptive function can shift cell homeostasis and contribute to the development of very distinct chronic pathologies such as psychostimulant abuse and tumor cell growth in cancers.

Differentially Expressed Genes in Period 2-Overexpressing Mice Striatum May Underlie Their Lower Sensitivity to Methamphetamine Addiction-Like Behavior

“…A previous study ( Kreple et al ., 2014 ) has correlated ASICs with drug addiction wherein the elimination of the ASIC1a-subtype was associated with the drug-induced plasticity proliferation. Interestingly, ASICs interact with sigma-1 receptors and influence Ca2+ influx and calcium homeostasis, which contributes to the development of psychostimulant abuse ( Soriani and Kourrich, 2019 ). Despite the lack of identified associations between Asic3 and addiction, several studies have mentioned other subtypes of ASICs to be involved in stimulant addiction, which could provide Asic3 a possible role in METH addiction.…”

Design, Radiosynthesis and Preliminary Biological Evaluation in Mice of a Brain-Penetrant 18F-Labelled σ2 Receptor Ligand

“…Radiochemical yield, radiochemical purity, and analyses of plasma and brain samples were assessed via reversed-phase HPLC (RP-HPLC) in gradient mode (0-10 min: 10% MeCN/20 mM NH 4 Molar activity was determined using analytical radio-HPLC with a Reprosil-Pur C18-AQ column (250 × 4.6 mm, 5 µm) and 42% MeCN/20 mM NH 4 OAc aq. as eluent at a flow rate of 1 mL•min −1 and UV detection at 208 nm.…”

“…Differences in the stereoselectivity, pharmacology, and molecular weight of guinea pig brain σ receptors and the binding sites of σ receptor ligands in PC12 cells, a tumor cell line derived from rat adrenal chromaffin cells, led to the designation of σ 1 and σ 2 receptors, respectively [ 2 ]. By contrast to the structurally and functionally thoroughly investigated and well described σ 1 receptor (for recent reviews of structure, function, and therapeutic potential, see, e.g., Tangui [ 3 ] or Soriani and Kourrich [ 4 ]), a profound characterization of the biology and a comprehensive understanding of the therapeutic potential of the σ 2 receptor were delayed mainly due to the absent identification of the protein and the coding gene. A significant step forward was the identification of progesterone receptor membrane component 1 (PGRMC1) as part of the protein complex containing the binding site of σ 2 receptor ligands, which was developed by Mach and colleagues in 2011 [ 5 ].…”

Structural and Functional Significance of the Endoplasmic Reticulum Unfolded Protein Response Transducers and Chaperones at the Mitochondria–ER Contacts: A Cancer Perspective

“…Evidence suggests that deregulation of σ1R may be involved in several events including apoptosis resistance, tumor growth, migration, invasive potency, angiogenesis, and cell response to the microenvironment ( Crottes et al, 2013 ). Indeed, σ1R overexpression occurs in distinct types of cancer ( Renaudo et al, 2004 ; Crottes et al, 2013 ; Soriani and Kourrich, 2019 ). In breast and colon cancers, σ1R overexpression occurs predominantly at the ER–mitochondria interface and correlates with an invasive and metastatic phenotype, whereas low expression levels are found in normal cells ( Aydar et al, 2006 ; Gueguinou et al, 2017 ).…”