Molecular events associated with the regulation of signaling by M2 muscarinic receptors.

Hosey MM, Pals-Rylaarsdam R, Lee KB, Roseberry AG, Benovic JL, Gurevich VV, B√ľnemann M
Life Sci. 1999 64 (6-7): 363-8

PMID: 10069497 · DOI:10.1016/s0024-3205(98)00575-x

Multiple events are associated with the regulation of signaling by the M2 muscarinic cholinergic receptors (mAChRs). Desensitization of the attenuation of adenylyl cyclase by the M2 mAChRs appears to involve agonist-dependent phosphorylation of M2 mAChRs by G-protein coupled receptor kinases (GRKs) that phosphorylate the receptors in a serine/threonine rich motif in the 3rd intracellular domain of the receptors. Mutation of residues 307-311 from TVSTS to AVAAA in this domain of the human M2 mAChR results in a loss of receptor/G-protein uncoupling and a loss of arrestin binding. Agonist-induced sequestration of receptors away from their normal membrane environment is also regulated by agonist-induced phosphorylation of the M2 mAChRs on the 3rd intracellular domain, but in HEK cells, the predominant pathway of internalization is not regulated by GRKs or arrestins. This pathway of internalization is not inhibited by a dominant negative dynamin, and does not appear to involve either clathrin coated pits or caveolae. The signaling of the M2 mAChR to G-protein regulated inwardly rectifying K channels (GIRKs) can be modified by RGS proteins. In HEK cells, expression of RGS proteins leads to a constitutive activation of the channels through a mechanism that depends on Gbetagamma. RGS proteins appear to increase the concentration of free Gbetagamma in addition to acting as GAPs. Thus multiple mechanisms acting at either the level of the M2 mAChRs or the G-proteins can contribute to the regulation of signaling via the M2 mAChRs.

MeSH Terms (25)

Adenylate Cyclase Toxin Amino Acid Substitution Arrestins Barium beta-Adrenergic Receptor Kinases Carbachol Cell Line Cyclic AMP-Dependent Protein Kinases Down-Regulation Genes, Dominant G Protein-Coupled Inwardly-Rectifying Potassium Channels GTP-Binding Proteins GTPase-Activating Proteins Humans Phosphorylation Potassium Channel Blockers Potassium Channels Potassium Channels, Inwardly Rectifying Proteins Receptor, Muscarinic M2 Receptors, Muscarinic RGS Proteins Signal Transduction Transfection Virulence Factors, Bordetella

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