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Updated: May 23, 2026

Simultaneous Electrophysiological Recording and Calcium Imaging of Suprachiasmatic Nucleus Neurons
Published on: December 8, 2013
Structural basis and physiological significance of non-canonical Gs coupling to the melatonin MT1 receptor
Atsuro Oishi1,2, Hiroyuki H Okamoto3, Keisuke Ikegami4,5
1Université Paris Cité, Institut Cochin, INSERM, CNRS, 75014, Paris, France. aoishi@ks.kyorin-u.ac.jp.
Abstract:
G protein-coupled receptors (GPCRs) transduce extracellular stimuli into intracellular signals by coupling to various heterotrimeric G proteins. However, the rules governing G protein preference remain largely elusive. MT1 and MT2 are prototypical Gi/o-coupled GPCRs responding to melatonin, a hormone secreted in a circadian manner. We show here that MT1, but not MT2, couples also to Gs proteins in vitro and activates the Gs/cAMP pathway upon long-term melatonin exposure in vivo, mimicking physiological dawn conditions. We solve the cryo-electron microscopy structure of the melatonin-MT1-Gs complex at 3.0 Å resolution, which reveals a distinct binding mode compared to the MT1-Gi complex. The third intracellular loop of MT1 emerges as a key stabilizer for Gs coupling. This structure of a GPCR primarily coupling to Gi, here in complex with Gs, provides structural and functional insights into G protein selectivity and circadian switch of G protein coupling.
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