Evidence that the σ 1 receptor is not directly coupled to G proteins

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