The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N -dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na ⁺ ) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

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.

Sigma-1 receptor (S1R) is a mammalian member of the ERG2 and sigma-1 receptor-like protein family (pfam04622). It has been implicated in drug addiction and many human neurological disorders, including Alzheimer and Parkinson diseases and amyotrophic lateral sclerosis. A broad range of synthetic small molecules, including cocaine, (+)-pentazocine, haloperidol, and small endogenous molecules such as N,N-dimethyltryptamine, sphingosine, and steroids, have been identified as regulators of S1R. However, the mechanism of activation of S1R remains obscure. Here, we provide evidence in vitro that S1R has ligand binding activity only in an oligomeric state. The oligomeric state is prone to decay into an apparent monomeric form when exposed to elevated temperature, with loss of ligand binding activity. This decay is suppressed in the presence of the known S1R ligands such as haloperidol, BD-1047, and sphingosine. S1R has a GXXXG motif in its second transmembrane region, and these motifs are often involved in oligomerization of membrane proteins. Disrupting mutations within the GXXXG motif shifted the fraction of the higher oligomeric states toward smaller states and resulted in a significant decrease in specific (+)-[³H]pentazocine binding. Results presented here support the proposal that S1R function may be regulated by its oligomeric state. Possible mechanisms of molecular regulation of interacting protein partners by S1R in the presence of small molecule ligands are discussed.

The retinal phosphodiesterase (PDE6) inhibitory γ-subunit (PDEγ) plays a central role in vertebrate phototransduction through alternate interactions with the catalytic αβ-subunits of PDE6 and the α-subunit of transducin (α _t ). Detailed structural analysis of PDEγ has been hampered by its intrinsic disorder. We present here the NMR solution structure of PDEγ, which reveals a loose fold with transient structural features resembling those seen previously in the x-ray structure of PDEγ _46–87 when bound to α _t in the transition-state complex. NMR mapping of the interaction between PDEγ _46–87 and the chimeric PDE5/6 catalytic domain confirmed that C-terminal residues 74–87 of PDEγ are involved in the association and demonstrated that its W70 indole group, which is critical for subsequent binding to α _t , is left free at this stage. These results indicate that the interaction between PDEγ and α _t during the phototransduction cascade involves the selection of preconfigured transient conformations.