Sigma receptor

Sigma receptors (σRs) have been recently referred in cancer pathophysiology. Three types of the opiate receptors were suggested and named by the corresponding greek symbol: μ for morphine, κ for ketazocine, and σ for (±)-SKF-10,047. Originally, two types of sigma receptors (σRs) were identified, sigma 1 receptor (σ1R), which was first cloned in 1996, and sigma 2 receptor (σ2R), which has not been cloned yet. One more type has been suggested, sigma 3 (σ3R), but it has not been defined adequately. σ1R is a polypeptide of molecular weight (MW) 29 kDa that comprises 223 amino acids and is not similar to known receptors, except for a 66.4% homology with a yeast C8-C7 sterol isomerase, they are important for the modulation of cation channels (K+, Na+ and Ca2+). σ1Rs are intracellular receptors that can translocate inside cells and act as chaperone proteins. Chaperone proteins are responsible for the correct folding of other proteins, during their synthesis or function. σ1Rs regulate Ca2+ signaling via the inositol triphosphate [IP3] receptor and, in particular, they ensure the Ca2+ signaling from endoplasmic reticulum (ER) into mitochondrion. Moreover, σ1Rs modulate K+ channels in pituitary and brain cells through G protein coupling or protein-protein interactions. 
The cell shrinkage, which is necessary for programmed cell death (apoptosis), is mediated through K+ loss. Moreover, σ1R is assumed to be involved in tumor genesis, as the corresponding receptor gene is a target of the oncogene c-Myc. The σ2 protein was initially characterized as the progesterone receptor membrane component 1 (PGRMC1).  In contrast to σ1Rs that dynamically translocate, σ2Rs are located in the lipid raft and are coupled with the PGRMC1 complex, EGFR, mTOR, caspases, and various ion channels. σ1R and σ2R have recently been involved in apoptosis (programmed cell death). σ1R and σ2R are highly expressed in cancer cells and up-regulated prior to mitosis, suggesting important cellular functions in cancer. σ1R antagonists deactivate the receptor activity, which is anti-apoptotic and neuroprotective and σ2R agonists stimulate the receptor activity and sensitizes cancer cells for apoptosis. Although there is considerable evidence of antiproliferative and cytotoxic activity for σ1R antagonists, σ2R agonists and mixed σ1R/σ2R ligands, the mechanism of action is still elusive.


1.Georgiadis MO,et al. Molecules. 2017;22(9):1408.