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 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.
Brea
José
J
Departamento de Farmacología, Instituto de Farmacia Industrial, Universidad de Santiago de Compostela, Spain.
Castro
Marián
M
Giraldo
Jesús
J
López-Giménez
Juan F
JF
Padín
Juan Fernando
JF
Quintián
Fátima
F
Cadavid
Maria Isabel
MI
Vilaró
Maria Teresa
MT
Mengod
Guadalupe
G
Berg
Kelly A
KA
Clarke
William P
WP
Vilardaga
Jean-Pierre
JP
Milligan
Graeme
G
Loza
Maria Isabel
MI
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D011487:Protein Conformation; D055503:Protein Multimerization; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D015398:Signal Transduction
D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists