@article{f0d092889d9247b7bf59cbeb3ce91c07,
title = "Discovery of ciliary G protein-coupled receptors regulating pancreatic islet insulin and glucagon secretion",
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 a and B cells. Loss of cilia disrupts B-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet a and B 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 a-and B-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 a and B cells is controlled by ciliary GPCRs providing new targets for diabetes.",
keywords = "A cells, B cells, Cilia, Diabetes, Glucagon, Glucose-stimulated insulin secretion, Insulin, Obesity, Pancreas",
author = "Wu, {Chien Ting} and Hilgendorf, {Keren I.} and Bevacqua, {Romina J.} and Yan Hang and Janos Demeter and Kim, {Seung K.} and Jackson, {Peter K.}",
note = "Funding Information: We acknowledge members of the Kim laboratory, especially Jonathan Lam and Dr. Sangbin Park, for helpful discussions and assistance with islet experiments. MIN6 cells were gifts from Professor Jun-ichi Miyazaki (Department of Stem Cell Regulation Research, Graduate School of Medicine, Osaka University, Osaka, Japan). We thank the Alberta Diabetes Institute Islet (ADI) Research Core, the Integrated Islet Distribution Program, the National Disease Research Interchange, and the International Institute for the Advancement of Medicine for islet and/or pancreas procurement, and especially the organ donors and their families. P.K.J. was supported by National Institutes of Health (NIH) grants R01GM11427604, R01HD085901, and R01GM12156503, and the Stanford Department of Research, Baxter Laboratory, and a Stanford Diabetes Research Center (SDRC) Pilot and Feasibility Research Grant (to P.K.J. and S.K.K.). K.I.H. is a Layton Family Fellow of the Damon Runyon Cancer Research Foundation (DRG-2210-14). R.J.B. was supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation in Israel (JDRF) (3-PDF-2018-584-A-N). Work in the Kim group was supported by NIH awards (R01 DK107507, R01 DK108817, U01 DK123743, and R01DK126482 to S.K.K.), and gift funding from Michelle and Steve Kirsch, the Reid family, the Schaffer family fund, the Snyder Foundation, two anonymous donors, and the Funding Information: JDRF Center of Excellence (to S.K.K. and M. Hebrok). Work here was also supported by NIH grant P30 DK116074 (to S.K.K.), and by the Stanford Islet Research Core, and Diabetes Genomics and Analysis Core of the Stanford Diabetes Research Center. Publisher Copyright: {\textcopyright} 2021 Cold Spring Harbor Laboratory Press. All rights reserved.",
year = "2021",
month = sep,
day = "1",
doi = "10.1101/GAD.348261.121",
language = "English (US)",
volume = "35",
pages = "1243--1255",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "17-18",
}