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Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells† † Electronic supplementary information (ESI) available: Figures, tables, methods, and detailed synthetic methods. See DOI: 10.1039/d1sc02527a

ABSTRACT: 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 Ca2+ 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. Optically-cleavable targeted ligands unite photocaged chemistry with genetic targeting to induce cell activity at defined membranes. OCT-PEA uncaging stiumlates β-cell activity via cell surface GPR55.

SUBMITTER: Tobias J

PROVIDER: S-EPMC8528030 | biostudies-literature |

REPOSITORIES: biostudies-literature

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