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A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction

  • Author(s): Xia, Z
  • Gray, JA
  • Compton-Toth, BA
  • Roth, BL
  • et al.
Abstract

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-HT2Areceptor possesses a canonical Type I PDZ-binding domain (X-Ser/Thr-X-Φ) 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-HT2Areceptor and regulates 5-HT2Areceptor-mediated signaling and trafficking in HEK-293 cells. Co-immunoprecipitation studies revealed that the native 5-HT2Areceptor, but not a mutant lacking the PDZ-binding domain, interacted directly with PSD-95. The association with PSD-95 enhanced 5-HT2Areceptor-mediated signal transduction, a novel action of PSD-95 on GPCRs. The augmentation of 5-HT2Areceptor signaling by PSD-95 was not accompanied by alteration in the kinetics of 5-HT2Areceptor desensitization but was associated with the inhibition of agonist-induced 5-HT2Areceptor internalization. Additional studies demonstrated that 5-HT2Areceptor 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-HT2Areceptors and possibly other GPCRs.

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