Evidence that the σ1 receptor is not directly coupled to G proteins

Sigma (sigma) receptors have been implicated in psychosis, cognition, neuroprotection, and locomotion in the central nervous system. The signal transduction mechanisms for a receptors have not been fully elucidated. In this study, we examined the possible coupling between sigma (1) receptors and heterotrimeric guanine nucleotide-binding proteins (G proteins) in rodent brain. In sigma (1) receptor-rich cerebellar membrane preparations, the competitive binding curves of two sigma (1) agonists, (+)pentazocine and 1S,2R-(-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (BD737), were unaffected by the addition of 10 muM guanosine-5'-O-(gamma -thio)-triphosphate (GTP gammaS). Neither (+)pentazocine (1-100 muM) nor BD737 (0.01-10 muM) stimulated GTPase activities significantly above basal levels in agonist-stimulated GTPase activity assays in cerebellar membranes. Furthermore, when using the method of agonist-stimulated [S-35]GTP gammaS binding as assessed by autoradiography, we did not observe significant stimulation of [S-35]GTP gammaS binding in rat brain sections by either (+)pentazocine or BD737. The above results demonstrate that the a, receptor is not likely be directly coupled to G proteins. (C) 2000 Elsevier Science B.V. All rights reserved.