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

Janelle M. Tobias, Gabriela Rajic, Alexander E.G. Viray, David Icka-Araki, James A. Frank

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 ano-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+activityviaphospholipase 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.

Original languageEnglish (US)
Pages (from-to)13506-13512
Number of pages7
JournalChemical Science
Volume12
Issue number40
DOIs
StatePublished - Oct 28 2021

ASJC Scopus subject areas

  • Chemistry(all)

Fingerprint

Dive into the research topics of 'Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells'. Together they form a unique fingerprint.

Cite this