Functional coupling of M muscarinic acetylcholine receptor to Gα in dorsolateral prefrontal cortex from patients with psychiatric disorders: a postmortem study.

Accumulating studies have implicated intracellular signaling through muscarinic acetylcholine receptors (mAChRs) in psychiatric illness. In the present study, carbamylcholine chloride (carbachol)-induced Gα and Gα activation was identified in postmortem human prefrontal cortical membranes. The following two sample cohorts were used: subjects [1], consisting of 40 controls without neuropsychiatric disorders, and subjects [2], consisting of 20 with bipolar disorder (BP), 20 major depressive disorder (MDD), 20 schizophrenia, and 20 controls, strictly sex- and age-matched. Carbachol-stimulated [S]GTPγS binding to human brain membranes was assessed by the two methods, i.e., conventional method using filtration techniques (Gα activation coupled to M/M mAChRs) applied to subjects [1], and [S]GTPγS binding/immuno precipitation assay (Gα activation coupled to M mAChR) applied to subjects [1] and [2]. The concentration eliciting the half-maximal effect (EC), maximum percent increase (%E), and slope factor were obtained from concentration-response curve of carbachol-induced Gα and Gα activation. The pEC values of both carbachol-induced Gα and Gα activations in subjects [1] were significantly correlated, though its implications or underlying molecular processes are unclear. The results of M mAChR-mediated Gα activation in subjects [2] indicated no significant disorder-specific alterations. However, the distribution patterns of the pEC values showed unequal variances among the groups. There was a significant inverse correlation between the %E values and the pEC values in subjects with schizophrenia, but not in those with BP or MDD, or controls. These data support the notion that schizophrenia patients consist of biologically heterogeneous subgroups with respect to M mAChR-mediated signaling pathways.