Evidence for distinct antagonist-revealed functional states of 5-HT_2A receptor homodimers

The serotonin (5-hydroxytryptamine, or 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 FRET and immunoprecipitation studies that the 5-HT2A-receptor homo-dimerized 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 receptor