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- W2022232781 abstract "M2 muscarinic receptors were purified as monomers from Sf9 cells and reconstituted as monomers in nanodiscs and as tetramers in phospholipid vesicles. In the absence of G proteins, monomers in solution and in nanodiscs appeared homogeneous (nH ≈ 1), as revealed by the inhibitory effect of agonists and antagonists on binding of the antagonist N-[3H]methylscopolamine. Reconstituted tetramers appeared homogenous to antagonists (nH > 0.80) and heterogeneous to agonists (nH < 0.80). The heterogeneity was modelled as two classes of sites (log…IC50(High), log…IC50(Low)) and quantified as the product of the difference in affinity (Δlog IC50) and the fraction of sites exhibiting higher affinity (FH) (i.e., FHΔlog…IC50). The resulting values correlated with the corresponding values of FHΔlog…IC50 and the intrinsic activities reported previously for binding and response, respectively, in natural membranes (p < 0.0001). In the presence of G proteins, reconstituted monomers and tetramers exhibited sensitivity to the guanyl nucleotide GMP-PNP. With tetramers, increasing concentrations of GMP-PNP caused an upward shift in the binding profile of the agonist oxotremorine-M, an effect that emerged from the model as an interconversion of labeled sites from high to low affinity with little or no change in affinity per se. With monomers, increasing concentrations of GMP-PNP caused a lateral rightward shift that emerged as an increase in the value of log…IC50. The vertical shift displayed by tetramers mirrors the patterns observed previously in native membranes, while the lateral shift displayed by monomers seems to be artefactual. This observation, taken together with the correlation among agonists between efficacy and the heterogeneity of reconstituted tetramers devoid of G protein, suggests that oligomers—most likely tetramers—are the functional unit of the M2 muscarinic receptor in nature. (Supported by HSFO and CIHR)" @default.
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- W2022232781 date "2013-01-01" @default.
- W2022232781 modified "2023-10-15" @default.
- W2022232781 title "Functional Comparison of Monomers and Tetramers of the M2 Muscarinic Receptor" @default.
- W2022232781 doi "https://doi.org/10.1016/j.bpj.2012.11.181" @default.
- W2022232781 hasPublicationYear "2013" @default.
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