Altered M₁ Muscarinic Acetylcholine Receptor (CHRM1)-Gα_q/11 Coupling in a Schizophrenia Endophenotype

Alterations in muscarinic acetylcholine receptor (CHRM) populations have been implicated in the pathology of schizophrenia. Here we have assessed whether the receptor function of the M 1 subtype (CHRM1) is altered in a sub-population of patients with schizophrenia, defined by marked (60-80%) reductions in cortical 3 H-pirenzepine (PZP) binding, and termed muscarinic receptor-deficit schizophrenia (MRDS). Using a 35 S-GTPγS-Gα q/11 immunocapture method we have assessed whether CHRM1 signalling in human cortex (Brodmann area 9 (BA9)) is altered in post mortem tissue from a MRDS group compared with a subgroup of patients with schizophrenia displaying normal PZP binding, and controls with no known history of psychiatric or neurological disorders. The CHRM agonist (oxotremorine-M) and a CHRM1-selective agonist (AC-42) increased Gα q/11 - 35 S-GTPγS binding, with AC-42 producing responses that were 50% of those maximally evoked by the full agonist, oxotremorine-M, in control and subgroups of patients with schizophrenia. However, the potency of oxotremorine-M to stimulate Gα q/11 - 35 S-GTPγS binding was significantly decreased in the MRDS group (pEC 50 (M)5.690.16) compared with the control group (6.170.10) and the non-MRDS group (6.050.07). The levels of Gα q/11 protein present in BA9 did not vary with diagnosis. Maximal oxotremorine-M-stimulated Gα q/11 - 35 S-GTPγS binding in BA9 membranes was significantly increased in the MRDS group compared with the control group. Similar, though non-statistically significant, trends were observed for AC-42. These data provide evidence that both orthosterically and allosterically acting CHRM agonists can stimulate a receptor-driven functional response ( 35 S-GTPγS binding to Gα q/11) in membranes prepared from post mortem human dorsolateral prefrontal cortex of patients with schizophrenia and controls. Furthermore, in a subgroup of patients with schizophrenia displaying markedly decreased PZP binding (MRDS) we have shown that although agonist potency may decrease, the efficacy of CHRM1-Gα q/11 coupling increases, suggesting an adaptative change in receptor-G protein coupling efficiency in this endophenotype of patients with schizophrenia.