Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells.

Autor:	Tobias JM; Vollum Institute, Oregon Health & Science University Portland OR USA frankja@ohsu.edu.; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University Portland OR USA.; Graduate Program in Physiology & Pharmacology, Oregon Health & Science University Portland OR USA., Rajic G; Vollum Institute, Oregon Health & Science University Portland OR USA frankja@ohsu.edu., Viray AEG; Vollum Institute, Oregon Health & Science University Portland OR USA frankja@ohsu.edu.; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University Portland OR USA., Icka-Araki D; Vollum Institute, Oregon Health & Science University Portland OR USA frankja@ohsu.edu.; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University Portland OR USA.; Graduate Program in Biomedical Sciences, Oregon Health & Science University Portland OR USA., Frank JA; Vollum Institute, Oregon Health & Science University Portland OR USA frankja@ohsu.edu.; Department of Chemical Physiology & Biochemistry, Oregon Health & Science University Portland OR USA.
Jazyk:	angličtina
Zdroj:	Chemical science [Chem Sci] 2021 Sep 15; Vol. 12 (40), pp. 13506-13512. Date of Electronic Publication: 2021 Sep 15 (Print Publication: 2021).
DOI:	10.1039/d1sc02527a
Abstrakt:	Fatty acid amides (FAAs) are a family of second-messenger lipids that target cannabinoid receptors, and are known mediators of glucose-stimulated insulin secretion from pancreatic β-cells. Due to the diversity observed in FAA structure and pharmacology, coupled with the expression of at least 3 different cannabinoid G protein-coupled receptors in primary and model β-cells, our understanding of their role is limited by our inability to control their actions in time and space. To investigate the mechanisms by which FAAs regulate β-cell excitability, we developed the Optically-Cleavable Targeted (OCT)-ligand approach, which combines the spatial resolution of self-labeling protein (SNAP-) tags with the temporal control of photocaged ligands. By linking a photocaged FAA to an o -benzylguanine (BG) motif, FAA signalling can be directed towards genetically-defined cellular membranes. We designed a probe to release palmitoylethanolamide (PEA), a GPR55 agonist known to stimulate glucose-stimulated insulin secretion (GSIS). When applied to β-cells, OCT-PEA revealed that plasma membrane GPR55 stimulates β-cell Ca 2+ activity via phospholipase C. Moving forward, the OCT-ligand approach can be translated to other ligands and receptors, and will open up new experimental possibilities in targeted pharmacology. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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