10.1177/1087057105277968ARTICLEOsmond et al.G Pr tein–Coupled Receptor HTS via ERK K 1/2: A Novel Platform

Discovery of novel agonists and antagonists for G protein–coupled receptors (GPCRs) relies heavily on cell-based assays be-cause determination of functional consequences of receptor engagement is often desirable. Currently, there are several key pa-rameters measured to achieve this, including mobilization of intracellular Ca2+ and formation of cyclic adenosine monophosphate or inositol triphosphate. However, no single assay platform is suitable for all situations, and all of the assays have limitations. The authors have developed a new high-throughput homogeneous assay platform for GPCR discovery as an alternative to current assays, which employs detection of phosphorylation of the key signaling molecule p42/44 MAP kinase (ERK 1/2). The authors show that ERK 1/2 is consistently activated in cells stimulated by Gq-coupled GPCRs and provides a new high-throughput platform for screening GPCR drug candidates. The activation of ERK 1/2 in Gq-coupled GPCR sys-tems generates comparable pharmacological data for receptor agonist and antagonist data obtained by other GPCR activation measurement techniques. (Journal of Biomolecular Screening 2005:730-737) W of sig wide sense cretio linked logica models. As a result, GPCRs provide the largest group of therapeu-tic targets, and molecules that target GPCRs constitute greater than 50 % 2 con het units: the α subunit, which carries a GDP/GTP binding site, and nac-the sed d to ated cel-een ese that each class induces. Gαs-coupled receptors lead to increased levels of cyclic adenosine monophosphate (cAMP) via the adenylate tein subunits.4 The dissociated βγ subunit can also modulate sev-or inhibition of, and regulation of ng programs mea-730 www.sbsonline