Evidence for Distinct Antagonist-Revealed Functional States of 5-Hydroxytryptamine2A Receptor Homodimers

被引：45

作者：

Brea, Jose ^{[1
]}

Castro, Marian ^{[1
]}

Giraldo, Jesus ^{[2
,3
]}

Lopez-Gimenez, Juan F. ^{[4
]}

Fernando Padin, Juan ^{[1
]}

Quintian, Fatima ^{[1
]}

Isabel Cadavid, Maria ^{[1
]}

Teresa Vilaro, Maria ^{[5
]}

Mengod, Guadalupe ^{[4
,5
]}

Berg, Kelly A. ^{[6
]}

Clarke, William P. ^{[6
]}

Vilardaga, Jean-Pierre ^{[7
,8
,9
]}

Milligan, Graeme

Isabel Loza, Maria ^{[1
]}

机构：

[1] Univ Santiago de Compostela, Dept Farmacol, Inst Farm Ind, Fac Farm, Santiago De Compostela, Spain

[2] Univ Autonoma Barcelona, Inst Neurociencies, Bellaterra, Spain

[3] Univ Autonoma Barcelona, Unitat Bioestadist, Bellaterra, Spain

[4] Univ Glasgow, Dept Biochem & Mol Biol, Glasgow, Lanark, Scotland

[5] IDIBAPS, Consejo Super Invest Cient, Inst Invest Biomed Barcelona, Dept Neurochem & Neuropharmacol, Barcelona, Spain

[6] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA

[7] Univ Pittsburgh, Med Ctr, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA

[8] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA

[9] Harvard Univ, Sch Med, Boston, MA USA

来源：

MOLECULAR PHARMACOLOGY | 2009年 / 75卷 / 06期

关键词：

PROTEIN-COUPLED RECEPTOR; RESONANCE ENERGY-TRANSFER; BETA-ADRENERGIC-RECEPTOR; TERNARY COMPLEX MODEL; INVERSE AGONISTS; LIGAND-BINDING; LIVING CELLS; BETA(2)-ADRENERGIC RECEPTOR; CONFORMATIONAL-CHANGES; MEMBRANE MICRODOMAINS;

D O I：

10.1124/mol.108.054395

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：1380 / 1391

页数：12

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