A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction.
The serotonin (5-hydroxytryptamine) 2A receptor (5-HT2A) is an important G protein-coupled receptor (GPCR) that mediates the effects of hallucinogens and is the target of a number of commonly prescribed medications including atypical antipsychotics, antidepressants, and anxiolytics. The 5-HT2A receptor possesses a canonical Type I PDZ-binding domain (X-Ser/Thr-X-Phi) at the carboxyl ... terminus and has been predicted, but never demonstrated, to interact with PDZ domain-containing proteins. We discovered that PSD-95, a prototypic PDZ domain-containing protein, directly associates with the 5-HT2A receptor and regulates 5-HT2A receptor-mediated signaling and trafficking in HEK-293 cells. Co-immunoprecipitation studies revealed that the native 5-HT2A receptor, but not a mutant lacking the PDZ-binding domain, interacted directly with PSD-95. The association with PSD-95 enhanced 5-HT2A receptor-mediated signal transduction, a novel action of PSD-95 on GPCRs. The augmentation of 5-HT2A receptor signaling by PSD-95 was not accompanied by alteration in the kinetics of 5-HT2A receptor desensitization but was associated with the inhibition of agonist-induced 5-HT2A receptor internalization. Additional studies demonstrated that 5-HT2A receptor and PSD-95 were co-localized in clusters on the cell surface of HEK-293 cells. Taken together, the present work elucidates novel roles for PSD-95 in regulating the functional activity and intracellular trafficking of 5-HT2A receptors and possibly other GPCRs.
Mesh Terms:
Amino Acid Motifs, Cell Line, DNA, Complementary, Dose-Response Relationship, Drug, Gene Expression Regulation, Humans, Hydrolysis, Microscopy, Fluorescence, Mutation, Nerve Tissue Proteins, Phosphatidylinositols, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein Transport, Receptor, Serotonin, 5-HT2A, Receptors, Serotonin, Signal Transduction, Time Factors, Transfection
Amino Acid Motifs, Cell Line, DNA, Complementary, Dose-Response Relationship, Drug, Gene Expression Regulation, Humans, Hydrolysis, Microscopy, Fluorescence, Mutation, Nerve Tissue Proteins, Phosphatidylinositols, Precipitin Tests, Protein Binding, Protein Structure, Tertiary, Protein Transport, Receptor, Serotonin, 5-HT2A, Receptors, Serotonin, Signal Transduction, Time Factors, Transfection
J. Biol. Chem.
Date: Jun. 13, 2003
PubMed ID: 12682061
View in: Pubmed Google Scholar
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