Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion
Open Access
- 12 August 2021
- journal article
- research article
- Published by Cold Spring Harbor Laboratory in Genes & Development
- Vol. 35 (17-18), 1243-1255
- https://doi.org/10.1101/gad.348261.121
Abstract
Multiple G protein-coupled receptors (GPCRs) are expressed in pancreatic islet cells, but the majority have unknown functions. We observed specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α and β cells. Loss of cilia disrupts β-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α and β cells, including FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and β-cell lines and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets relocalized ciliary FFAR4 and PTGER4 and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α and β cells is controlled by ciliary GPCRs providing new targets for diabetes.Keywords
Funding Information
- National Institutes of Health (R01GM11427604, R01HD085901, R01GM12156503)
- Stanford Diabetes Research Center (Pilot and Feasibility Research Grant)
- Damon Runyon Cancer Research Foundation (DRG-2210-14)
- Juvenile Diabetes Research Foundation in Israel (3-PDF-2018-584-A-N)
- NIH (R01 DK107507, R01 DK108817, U01 DK123743, R01DK126482)
- Michelle and Steve Kirsch
- Reid family
- Schaffer family fund
- Snyder Foundation
- JDRF Center of Excellence
- NIH (P30 DK116074)
- Stanford Islet Research Core
- Diabetes Genomics and Analysis Core
- Stanford Diabetes Research Center
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