Altered M sub(1) Muscarinic Acetylcholine Receptor (CHRM1)-G alpha sub(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 sub(1) subtype (CHRM1) is altered in a sub-population of patients with schizophrenia, defined by marked (60-80%) reductions in cortical [ super(3)H]-pirenzepine (PZP) binding, and termed 'muscarinic receptor-deficit schizophrenia' (MRDS). Using a [ super(35)S]-GTP gamma S-G alpha sub(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 G alpha sub(q/11)-[ super(35) S]-GTP gamma S binding, with AC-42 producing responses that were similar to 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 G alpha sub(q/11)-[ super(35) S]-GTP gamma S binding was significantly decreased in the MRDS group (pEC sub(50) (M)=5.69 plus or minus 0.16) compared with the control group (6.17 plus or minus 0.10) and the non-MRDS group (6.05 plus or minus 0.07). The levels of G alpha sub(q/11) protein present in BA9 did not vary with diagnosis. Maximal oxotremorine-M-stimulated G alpha sub(q/11)-[ super(35) S]-GTP gamma S 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 ([ super(35)S]-GTP gamma S binding to G alpha sub(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-G alpha sub(q/11) coupling increases, suggesting an adaptative change in receptor-G protein coupling efficiency in this endophenotype of patients with schizophrenia.Neuropsychopharmacology (2009) 34, 2156-2166; doi:10.1038/npp.2009.41