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J Biol Chem, Vol. 274, Issue 47, 33671-33676, November 19, 1999

Trafficking of M₂ Muscarinic Acetylcholine Receptors

From the Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611

Internalization is an important mechanism regulating the agonist-dependent responses of G-protein-coupled receptors. The internalization of the M₂ muscarinic cholinergic receptors (mAChR) in HEK293 cells has been demonstrated to occur by an unknown mechanism that is independent of arrestins and dynamin. In this study we examined various aspects of the trafficking of the M₂ mAChR in HEK293 cells to characterize this unknown pathway of internalization. Internalization of the M₂ mAChR was rapid and extensive, but prolonged incubation with agonist did not lead to appreciable down-regulation (a decrease in total receptor number) of the receptors. Recovery of M₂ mAChRs to the cell surface following agonist-mediated internalization was a very slow process that contained protein synthesis-dependent and -independent components. The protein synthesis-dependent component of the recovery of receptors to the cell surface did not appear to reflect a requirement for synthesis of new receptors, as no changes in total receptor number were observed either in the presence or absence of cycloheximide. Phosphorylation of the M₂ mAChR did not appear to influence the rate or extent of the recovery of receptors to the cell surface, as the recovery of a phosphorylation-deficient mutant M₂ mAChR, the N,C_Ala-8 mutant, was similar to the recovery of the wild type M₂ mAChR. Finally, the constitutive, nonagonist-dependent internalization and recycling of the M₂ mAChR was very slow and also contained protein synthesis-dependent and -independent components, suggesting that a similar pathway controls the recovery from agonist-dependent and -independent internalization. Overall, these data demonstrated a variety of previously unappreciated facets involved in the regulation of M₂ mAChRs.

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