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Title: Altered M1 Muscarinic Acetylcholine Receptor (CHRM1)-Gαq/11 Coupling in a Schizophrenia Endophenotype
Authors: Salah-Uddin, Hasib
Scarr, Elizabeth
Pavey, Geoffrey
Harris, Kriss
Hagan, Jim J.
Dean, Brian
Challiss, R. A. John
Watson, Jeannette M.
First Published: Aug-2009
Publisher: Nature Publishing Group
Citation: Neuropsychopharmacology, 2009, 34 (9), pp. 2156–2166.
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.
DOI Link: 10.1038/npp.2009.41
ISSN: 0893-133X
Type: Article
Rights: This is the author's final draft of the paper published as Neuropsychopharmacology, 2009, 34 (9), pp. 2156–2166. The final version is available from Doi: 10.1038/npp.2009.41
Appears in Collections:Published Articles, Dept. of Cell Physiology and Pharmacology

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