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(Received for publication, February 24, 1997, and in revised form, March 27, 1997)
From the Department of Molecular Pharmacology and Biological
Chemistry, Northwestern University Medical School,
Chicago, Illinois 60611
Short term exposure of m2 muscarinic
acetylcholine receptors (m2 mAChRs) to agonist causes a rapid
phosphorylation of the activated receptors, followed by a profound loss
in the ability of the m2 mAChR to activate its signaling pathways. We
have used site-directed mutagenesis to identify two clusters of Ser/Thr residues in the third intracellular loop of the m2 mAChR that can serve
as redundant targets for agonist-dependent phosphorylation. Mutation of both clusters of Ser/Thr residues to alanines abolished agonist-dependent phosphorylation, while wild-type levels
of m2 mAChR phosphorylation were observed in mutant receptors with only one or the other cluster mutated. However, the functional effects of
phosphorylation of these two "redundant" clusters were not equivalent. No receptor desensitization was observed in an m2 mAChR
with residues Thr307-Ser311 mutated to
alanine residues. In contrast, mutation of the other Ser/Thr cluster,
residues Ser286-Ser290, to alanines produced a
receptor that continued to desensitize. Internalization of the m2 mAChR
was promoted by phosphorylation of either cluster, suggesting that
distinct mechanisms with unique structural requirements act downstream
of m2 mAChR phosphorylation to mediate receptor desensitization and
receptor internalization.
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