Asuka Inoue

Sep 7, 2024 | nature.com | Alexei Sirbu |Marc Bathe-Peters |Asuka Inoue |Martin J. Lohse |Paolo Annibale |Jothi L. M. Kumar

G protein-coupled receptors’ conformational landscape can be affected by their local, microscopic interactions within the cell plasma membrane. We employ here a pleiotropic stimulus, namely osmotic swelling, to alter the cortical environment within intact cells and monitor the response in terms of receptor function and downstream signaling. We observe that in osmotically swollen cells the β2-adrenergic receptor, a prototypical GPCR, favors an active conformation, resulting in cAMP transient responses to adrenergic stimulation that have increased amplitude. The results are validated in primary cell types such as adult cardiomyocytes, a model system where swelling occurs upon ischemia-reperfusion injury. Our results suggest that receptors’ function is finely modulated by their biophysical context, and specifically that osmotic swelling acts as a potentiator of downstream signaling, not only for the β2-adrenergic receptor, but also for other receptors, hinting at a more general regulatory mechanism. Osmotic swelling alters the local membrane environment, activating several GPCRs. Here the authors show that osmotic swelling enhances ligand-dependent signalling of β2-AR: this suggests regulatory mechanisms for GPCRs via their biophysical context.

Jun 7, 2023 | nature.com | Asuka Inoue

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Jun 7, 2023 | nature.com | Asuka Inoue |Miquel Pons |Scott A. Robson |Daniel Scott |Paul Gooley |Fabian Bumbak | +1 more

AbstractThe neurotensin receptor 1 (NTS1) is a G protein-coupled receptor (GPCR) with promise as a drug target for the treatment of pain, schizophrenia, obesity, addiction, and various cancers. A detailed picture of the NTS1 structural landscape has been established by X-ray crystallography and cryo-EM and yet, the molecular determinants for why a receptor couples to G protein versus arrestin transducers remain poorly defined.