Identification of Two Serine Residues Essential for Agonist-Induced 5-HT2A Receptor Desensitization
| Autor: | Beth Ann Compton-Toth, John A. Gray, Bryan L. Roth |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Threonine
Serotonin medicine.medical_treatment Molecular Sequence Data Biology Phosphatidylinositols Transfection Biochemistry Serine Homologous desensitization Phorbol Esters medicine Animals Humans Receptor Serotonin 5-HT2A Amino Acid Sequence Enzyme Inhibitors Receptor Cells Cultured Protein Kinase C Protein kinase C G protein-coupled receptor Desensitization (medicine) G protein-coupled receptor kinase Recombinant Proteins Rats Serotonin Receptor Agonists Quipazine Amino Acid Substitution Receptors Serotonin Phosphorylation |
| Zdroj: | Biochemistry. 42:10853-10862 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi035061z |
| Popis: | 5-HT(2A) serotonin receptors represent the principal molecular targets for LSD-like hallucinogens and atypical antipsychotic drugs. It has been proposed that a dysregulation of 5-HT(2A) 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-HT(2A) 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-HT(2A) receptors requires the presence of two nonconserved serine residues located in distinct intracellular loops. |
| Databáze: | OpenAIRE |
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