The Oligomeric States of the Purified Sigma-1 Receptor Are Stabilized by Ligands

作者：K. Gromek, Fabian P. Suchy, H. Meddaugh, R. Wrobel, Loren M. LaPointe, U. Chu, J. Primm, A. Ruoho, A. Senes, B. Fox · 发表于：Journal of Biological Chemistry · 年份：2014 · DOI：10.1074/jbc.M113.537993 · 被引用次数：102 · 研究领域：Medicine、Chemistry

Background: Sigma-1 receptor (S1R) is an integral membrane ligand-binding receptor. Results: Gel filtration chromatography revealed oligomeric states that are stabilized by ligand binding and destabilized by mutations in the GXXXG integral membrane dimerization domain. Conclusion: Purified S1R binds small molecule ligands as an oligomer but not as a monomer. Significance: The results provide new insight into the function of S1R with ligands and proteins partners. 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...