Abstract
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 M1 subtype (CHRM1) is altered in a sub-population of patients with schizophrenia, defined by marked (60–80%) reductions in cortical [3H]-pirenzepine (PZP) binding, and termed ‘muscarinic receptor-deficit schizophrenia’ (MRDS). Using a [35S]-GTPγS-Gαq/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 Gαq/11-[35S]-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 Gαq/11-[35S]-GTPγS binding was significantly decreased in the MRDS group (pEC50 (M)=5.69±0.16) compared with the control group (6.17±0.10) and the non-MRDS group (6.05±0.07). The levels of Gαq/11 protein present in BA9 did not vary with diagnosis. Maximal oxotremorine-M-stimulated Gαq/11-[35S]-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 ([35S]-GTPγS binding to Gαq/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-Gαq/11 coupling increases, suggesting an adaptative change in receptor-G protein coupling efficiency in this endophenotype of patients with schizophrenia.
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Acknowledgements
We gratefully acknowledge Drs CH Davies and MD Wood (GlaxoSmithKline) for their comments on earlier drafts of the paper and Drs FJ Ehlert (University of California, Irvine, CA, USA) and JR Traynor (University of Michigan, Ann Arbor, MI, USA) for their discussions concerning the interpretation of curve-fitting data. This work was funded in part by a collaboration grant from GlaxoSmithKline (to RAJC). BD is an NHMRC Senior Research Fellow (Level B: 400016) and this work was supported in part by Operational Infrastructure Support (OIS) from the Victorian State Government. ES is a Royce Abbey Postdoctoral Fellow, supported by the Australian Rotary Health Research Fund.
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The authors have no financial or competing interests to declare, except that ES received travel support from GlaxoSmithKline (in 2007) and an honorarium for a clinical presentation from AstraZeneca (in 2005).
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Salah-Uddin, H., Scarr, E., Pavey, G. et al. Altered M1 Muscarinic Acetylcholine Receptor (CHRM1)-Gαq/11 Coupling in a Schizophrenia Endophenotype. Neuropsychopharmacol 34, 2156–2166 (2009). https://doi.org/10.1038/npp.2009.41
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DOI: https://doi.org/10.1038/npp.2009.41
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