Evidence for distinct antagonist-revealed functional states of 5-hydroxytryptamine2A receptor homodimers

José Brea, Marián Castro, Jesús Giraldo, Juan F. López-Giménez, Juan Fernando Padín, Fátima Quintián, Maria Isabel Cadavid, Maria Teresa Vilaró, Guadalupe Mengod, Kelly A. Berg, William P. Clarke, Jean Pierre Vilardaga, Graeme Milligan, Maria Isabel Loza

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44 Scopus citations

Abstract

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-HT2A-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-HT2A receptor-mediated functions in a pathway-specific manner, explained here by a new model of multiple active interconvertible conformations at dimeric receptors.

Original languageEnglish (US)
Pages (from-to)1380-1391
Number of pages12
JournalMolecular pharmacology
Volume75
Issue number6
DOIs
StatePublished - Jun 2009

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Brea, J., Castro, M., Giraldo, J., López-Giménez, J. F., Padín, J. F., Quintián, F., Cadavid, M. I., Vilaró, M. T., Mengod, G., Berg, K. A., Clarke, W. P., Vilardaga, J. P., Milligan, G., & Loza, M. I. (2009). Evidence for distinct antagonist-revealed functional states of 5-hydroxytryptamine2A receptor homodimers. Molecular pharmacology, 75(6), 1380-1391. https://doi.org/10.1124/mol.108.054395