Evidence for distinct antagonist-revealed functional states of 5-hydroxytryptamine(2A) receptor homodimers

The serotonin (5-hydroxytryptamine; 5-HT) 2A receptor is a cell surface class A G protein-coupled receptor that regulates a multitude of physiological functions of the body and is a target for antipsychotic drugs. Here we found by means of fluorescence resonance energy transfer and immunoprecipitati...

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Published in:Molecular pharmacology 2009-06, Vol.75 (6), p.1380-1391
Main Authors: Brea, José, Castro, Marián, Giraldo, Jesús, López-Giménez, Juan F, Padín, Juan Fernando, Quintián, Fátima, Cadavid, Maria Isabel, Vilaró, Maria Teresa, Mengod, Guadalupe, Berg, Kelly A, Clarke, William P, Vilardaga, Jean-Pierre, Milligan, Graeme, Loza, Maria Isabel
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cricetinae
Cricetulus
Fluorescence Resonance Energy Transfer
Humans
Immunoprecipitation
Models, Biological
Protein Conformation
Protein Multimerization
Receptor, Serotonin, 5-HT2A - physiology
Serotonin 5-HT2 Receptor Antagonists
Signal Transduction
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Summary:The serotonin (5-hydroxytryptamine; 5-HT) 2A receptor is a cell surface class A G protein-coupled receptor that regulates a multitude of physiological functions of the body and is a target for antipsychotic drugs. Here we found by means of fluorescence resonance energy transfer and immunoprecipitation studies that the 5-HT(2A)-receptor homodimerized in live cells, which we linked with its antagonist-dependent fingerprint in both binding and receptor signaling. Some antagonists, like the atypical antipsychotics clozapine and risperidone, differentiate themselves from others, like the typical antipsychotic haloperidol, antagonizing these 5-HT(2A) receptor-mediated functions in a pathway-specific manner, explained here by a new model of multiple active interconvertible conformations at dimeric receptors.
ISSN:1521-0111
DOI:10.1124/mol.108.054395