Distinct agonist regulation of muscarinic acetylcholine M2-M3 heteromers and their corresponding homomers

Aslanoglou, D., Alvarez-Curto, E. , Marsango, S. and Milligan, G. (2015) Distinct agonist regulation of muscarinic acetylcholine M2-M3 heteromers and their corresponding homomers. Journal of Biological Chemistry, 290(23), pp. 14785-14796. (doi: 10.1074/jbc.M115.649079) (PMID:25918156) (PMCID:PMC4505543)

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Each subtype of the muscarinic receptor family of G protein-coupled receptors is activated by similar concentrations of the neurotransmitter acetylcholine or closely related synthetic analogs such as carbachol. However, pharmacological selectivity can be generated by the introduction of a pair of mutations to produce Receptor Activated Solely by Synthetic Ligand (RASSL) forms of muscarinic receptors. These display loss of potency for acetylcholine/carbachol alongside a concurrent gain in potency for the ligand clozapine N-oxide. Co-expression of a form of wild type human M2 and a RASSL variant of the human M3 receptor resulted in concurrent detection of each of M2-M2 and M3-M3 homomers alongside M2-M3 heteromers at the surface of stably transfected Flp-InTM T-RExTM 293 cells. In this setting occupancy of the receptors with a muscarinic antagonist was without detectable effect on any of the muscarinic oligomers. However, selective agonist occupancy of the M2 receptor resulted in enhanced M2-M2 homomer interactions but decreased M2-M3 heteromer interactions. By contrast, selective activation of the M3 RASSL receptor did not significantly alter either M3-M3 homomer or M2-M3 heteromer interactions. Selectively targeting closely related receptor oligomers may provide novel therapeutic opportunities.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Alvarez-Curto, Dr Elisa and Milligan, Professor Graeme and Marsango, Dr Sara
Authors: Aslanoglou, D., Alvarez-Curto, E., Marsango, S., and Milligan, G.
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN (Online):1083-351X

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656901The organisational structure of class A GPCRs: Implications for pharmacology, function and therapeutic regulationGraeme MilliganMedical Research Council (MRC)MR/L023806/1RI MOLECULAR CELL & SYSTEMS BIOLOGY
510631The organisational structure of class A GPCRs: implications for function and drug designGraeme MilliganMedical Research Council (MRC)G0900050RI NEUROSCIENCE & PSYCHOLOGY