PT - JOURNAL ARTICLE AU - Uyen Chu AU - Arnold E. Ruoho TI - Biochemical Pharmacology of the Sigma-1 Receptor AID - 10.1124/mol.115.101170 DP - 2015 Jan 01 TA - Molecular Pharmacology PG - mol.115.101170 4099 - http://molpharm.aspetjournals.org/content/early/2015/11/12/mol.115.101170.short 4100 - http://molpharm.aspetjournals.org/content/early/2015/11/12/mol.115.101170.full AB - The Sigma-1 receptor (S1R) is a 223 amino acid two transmembrane (TM) pass protein. It is a non ATP-binding non glycosylated ligand-regulated molecular chaperone of unknown 3-dimensional structure. The S1R is resident to eukaryotic mitochondrial associated endoplasmic reticulum and plasma membranes with broad functions that regulate cellular calcium homeostasis and reduce oxidative stress. Several multi-tasking functions of the S1R are underwritten by chaperone mediated direct (and indirect) interactions with ion channels, G-protein coupled receptors and cell signaling molecules involved in the regulation of cell growth. The S1R is a promising drug target for the treatment of several neurodegenerative diseases related to cellular stress. In vitro and in vivo functional and molecular characteristics of the S1R and its interactions with endogenous and synthetic small molecules have been discovered by the use of pharmacological, biochemical, biophysical and molecular biology approaches. The S1R exists in monomer, dimer, tetramer, hexamer/octamer and higher oligomeric forms that may be important determinants in defining the pharmacology and mechanism(s) of action of the S1R. A canonical GXXXG in putative TM2 is important for S1R oligomerization. The ligand binding regions of S1R have been identified to include portions of TM2 and the TM proximal regions of the C-terminus. Some client protein chaperone functions and interactions with the co chaperone GRP-78 (BIP) involve the C-terminus. Based on its biochemical features and mechanisms of chaperone action the possibility that the S1R is a member of the small heat shock protein (sHSP) family is discussed.