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Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells
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 diff...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528030/ https://www.ncbi.nlm.nih.gov/pubmed/34777770 http://dx.doi.org/10.1039/d1sc02527a |
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author | Tobias, Janelle M. Rajic, Gabriela Viray, Alexander E. G. Icka-Araki, David Frank, James A. |
author_facet | Tobias, Janelle M. Rajic, Gabriela Viray, Alexander E. G. Icka-Araki, David Frank, James A. |
author_sort | Tobias, Janelle M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8528030 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-85280302021-11-12 Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells Tobias, Janelle M. Rajic, Gabriela Viray, Alexander E. G. Icka-Araki, David Frank, James A. Chem Sci Chemistry 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. The Royal Society of Chemistry 2021-09-15 /pmc/articles/PMC8528030/ /pubmed/34777770 http://dx.doi.org/10.1039/d1sc02527a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Tobias, Janelle M. Rajic, Gabriela Viray, Alexander E. G. Icka-Araki, David Frank, James A. Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells |
title | Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells |
title_full | Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells |
title_fullStr | Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells |
title_full_unstemmed | Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells |
title_short | Genetically-targeted photorelease of endocannabinoids enables optical control of GPR55 in pancreatic β-cells |
title_sort | genetically-targeted photorelease of endocannabinoids enables optical control of gpr55 in pancreatic β-cells |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528030/ https://www.ncbi.nlm.nih.gov/pubmed/34777770 http://dx.doi.org/10.1039/d1sc02527a |
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