AGAP1/AP-3-dependent endocytic recycling of M5 muscarinic receptors promotes dopamine release.

TitleAGAP1/AP-3-dependent endocytic recycling of M5 muscarinic receptors promotes dopamine release.
Publication TypeJournal Article
Year of Publication2010
AuthorsBendor J, Lizardi-Ortiz JE, Westphalen RI, Brandstetter M, Hemmings HC, Sulzer D, Flajolet M, Greengard P
JournalEMBO J
Date Published2010 Aug 18
KeywordsAdaptor Protein Complex 3, Amino Acid Sequence, Animals, Cells, Cultured, Corpus Striatum, Dopamine, Endocytosis, Female, GTPase-Activating Proteins, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Neurons, Protein Structure, Tertiary, Rats, Rats, Sprague-Dawley, Receptor, Muscarinic M5, Sequence Alignment

Of the five mammalian muscarinic acetylcholine (ACh) receptors, M(5) is the only subtype expressed in midbrain dopaminergic neurons, where it functions to potentiate dopamine release. We have identified a direct physical interaction between M(5) and the AP-3 adaptor complex regulator AGAP1. This interaction was specific with regard to muscarinic receptor (MR) and AGAP subtypes, and mediated the binding of AP-3 to M(5). Interaction with AGAP1 and activity of AP-3 were required for the endocytic recycling of M(5) in neurons, the lack of which resulted in the downregulation of cell surface receptor density after sustained receptor stimulation. The elimination of AP-3 or abrogation of AGAP1-M(5) interaction in vivo decreased the magnitude of presynaptic M(5)-mediated dopamine release potentiation in the striatum. Our study argues for the presence of a previously unknown receptor-recycling pathway that may underlie mechanisms of G-protein-coupled receptor (GPCR) homeostasis. These results also suggest a novel therapeutic target for the treatment of dopaminergic dysfunction.

Alternate JournalEMBO J.
PubMed ID20664521
PubMed Central IDPMC2924642
Grant ListDA 10044 / DA / NIDA NIH HHS / United States
P01 DA010044 / DA / NIDA NIH HHS / United States
R01 GM058055 / GM / NIGMS NIH HHS / United States
T32DA016224 / DA / NIDA NIH HHS / United States