Identification of two serine residues essential for agonist-induced 5-HT2A receptor desensitization

John Gray, Beth A. Compton-Toth, Bryan L. Roth

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

5-HT2A serotonin receptors represent the principal molecular targets for LSD-like hallucinogens and atypical antipsychotic drugs. It has been proposed that a dysregulation of 5-HT2A receptor-mediated signaling may contribute to the pathogenesis of schizophrenia and related diseases. A major mechanism for the attenuation of GPCR signaling following agonist activation typically involves the phosphorylation of serine and/or threonine residues by various kinases. Ser/Thr phosphorylation leads to the binding of accessory proteins and the uncoupling of the G proteins, thereby preventing further signaling. The molecular mechanisms by which 5-HT 2A receptors are desensitized are unknown, and to date, no residues essential for agonist-mediated desensitization have been identified. Thus, we mutated, individually or in groups, all of the 37 serines and threonines in the cytoplasmic domains of the 5-HT2A receptor and assessed the effects of these mutations on agonist-mediated desensitization. We discovered that mutation of two residues, S421 in the C-terminal tail and S188 in the second intracellular loop, to alanine resulted in a significant block of agonist-induced desensitization. Intriguingly, a single-nucleotide polymorphism, of unreported frequency, at the S421 locus has been reported (S421F); the S421F mutation, like the S421A mutation, significantly attenuated agonist-mediated desensitization. Taken together, these findings indicate that the process of agonist-mediated desensitization of 5-HT2A receptors requires the presence of two nonconserved serine residues located in distinct intracellular loops.

Original languageEnglish (US)
Pages (from-to)10853-10862
Number of pages10
JournalBiochemistry
Volume42
Issue number36
DOIs
StatePublished - Sep 16 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry

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