The molecular basis of oligomeric organization of the human M3 muscarinic acetylcholine receptor

Molecular Pharmacology
María José Varela ListeGraeme Milligan

Abstract

G protein-coupled receptors, including the M3 muscarinic acetylcholine receptor, can form homo-oligomers. However, the basis of these interactions and the overall organizational structure of such oligomers are poorly understood. Combinations of site-directed mutagenesis and homogenous time-resolved fluorescence resonance energy transfer studies that assessed interactions between receptor protomers at the surface of transfected cells indicated important contributions of regions of transmembrane domains I, IV, V, VI, and VII as well as intracellular helix VIII to the overall organization. Molecular modeling studies based on both these results and an X-ray structure of the inactive state of the M3 receptor bound by the antagonist/inverse agonist tiotropium were then employed. The results could be accommodated fully by models in which a proportion of the cell surface M3 receptor population is a tetramer with rhombic, but not linear, orientation. This is consistent with previous studies based on spectrally resolved, multiphoton fluorescence resonance energy transfer. Modeling studies furthermore suggest an important role for molecules of cholesterol at the dimer + dimer interface of the tetramer, which is consistent with the presenc...Continue Reading

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Citations

Apr 30, 2016·Blood·Marvin T Nieman
May 2, 2015·The Journal of Biological Chemistry·Sara MarsangoGraeme Milligan
Apr 16, 2016·The Journal of Biological Chemistry·John D PedianiGraeme Milligan
Apr 27, 2019·Frontiers in Pharmacology·Estefanía MorenoEnric Canela
Mar 7, 2021·International Journal of Molecular Sciences·Jan Jakubík, Esam E El-Fakahany
Aug 30, 2018·The Journal of Physical Chemistry. B·Samuel A Ramirez, Chad Leidy

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