1. ¹Department of Cell Physiology & Pharmacology, Henry Wellcome Building, University of Leicester, Leicester, UK
2. ²Rebecca L Cooper Research Laboratories, Mental Health Research Institute, Parkville, Victoria, Australia
3. ³Centre for Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
4. ⁴Discovery Analytics, GlaxoSmithKline, Stevenage, Hertfordshire, UK
5. ⁵Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK
6. ⁶Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
7. ⁷Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia
8. ⁸Department of Psychological Medicine, Monash University, Melbourne, Victoria, Australia

Correspondence: Professor RAJ Challiss, Department of Cell Physiology & Pharmacology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester, LE1 9HN, UK. Tel: +44 0 116 229 7146; Fax: +44 0 116 252 5045; E-mail: jc36@leicester.ac.uk

⁹Joint senior authors

Received 17 October 2008; Revised 23 March 2009; Accepted 23 March 2009; Published online 29 April 2009.

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]-GTPS-G_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_q/11-[³⁵S]-GTPS 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 G_q/11-[³⁵S]-GTPS binding was significantly decreased in the MRDS group (pEC₅₀ (M)=5.690.16) compared with the control group (6.170.10) and the non-MRDS group (6.050.07). The levels of G_q/11 protein present in BA9 did not vary with diagnosis. Maximal oxotremorine-M-stimulated G_q/11-[³⁵S]-GTPS 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]-GTPS binding to G_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_q/11 coupling increases, suggesting an adaptative change in receptor-G protein coupling efficiency in this endophenotype of patients with schizophrenia.