Research ArticleGPCR SIGNALING

Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations

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Sci. Signal.  09 Oct 2018:
Vol. 11, Issue 551, eaan1188
DOI: 10.1126/scisignal.aan1188

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Ultrasensitivity of GPCRs

Most analyses of signaling through G protein–coupled receptors (GPCRs) are performed using nanomolar or micromolar concentrations of ligand. Civciristov et al. found that femtomolar concentrations of ligand activated signaling by the endogenous β2-adrenergic receptor (β2AR) and muscarinic acetylcholine receptor M3 (M3R) in several cell types. Such ultralow concentrations of ligand stimulated signaling that was qualitatively distinct from that elicited by high concentrations and depended on activation of preassembled GPCR complexes. In contrast, high concentrations of ligand elicited signaling through GPCRs that were not part of complexes in addition to those in preassembled complexes. Such qualitative differences in signaling elicited by different ligand concentrations suggest that low doses of GPCR-targeting drugs could have therapeutic effects and may have implications for the mechanisms of action and side effects of these drugs.