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Pharmacological Assessment of M1 Muscarinic Acetylcholine Receptor-Gq/11 Protein Coupling in Membranes Prepared from Postmortem Human Brain Tissue

By Hasib Salah-Uddin, David R. Thomas, Ceri H. Davies, Jim J. Hagan, Martyn D. Wood, Jeannette M. Watson and R.A. John Challiss


This paper was published as Journal of Pharmacology and Experimental Therapeutics, 2008, 325 (3), pp. 869-874. It is available from Doi: 10.1124/jpet.108.137968Metadata only entryUsing a selective Gαq/11 protein antibody capture guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding approach, it has been possible to perform a quantitative pharmacological examination of the functional activity of the M1 muscarinic acetylcholine receptor (mAChR) in membranes prepared from human postmortem cerebral cortex. Oxotremorine-M caused a ≥2-fold increase in [35S]GTPγS-Gαq/11 binding with a pEC50 of 6.06 ± 0.16 in Brodmann's areas 23 and 25 that was almost completely inhibited by preincubation of membranes with the M1 mAChR subtype-selective antagonist muscarinic toxin-7. In addition, the orthosteric and allosteric agonists, xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine] and AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine hydrogen chloride), increased [35S]-GTPγS-Gαq/11 binding, but with reduced intrinsic activities, inducing maximal responses that were 42 ± 1 and 44 ± 2% of the oxotremorine-M-induced response, respectively. These data indicate that the M1 receptor is the predominant mAChR subtype coupling to the Gαq/11 G protein in these brain regions and that it is possible to quantify the potency and intrinsic activity of full and partial M1 mAChR receptor agonists in postmortem human brain using a selective Gαq/11 protein antibody capture [35S]GTPγS binding assay

Publisher: American Society for Pharmacology and Experimental Therapeutics (ASPET)
Year: 2008
DOI identifier: 10.1124/jpet.108.137968
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