@article{84d0b1c2bea148779dade1a5206c8192,
title = "ELKS/Voltage-Dependent Ca2+ Channel-β Subunit Module Regulates Polarized Ca2+ Influx in Pancreatic β Cells",
abstract = "Pancreatic β cells secrete insulin by Ca2+-triggered exocytosis. However, there is no apparent secretory site similar to the neuronal active zones, and the cellular and molecular localization mechanism underlying polarized exocytosis remains elusive. Here, we report that ELKS, a vertebrate active zone protein, is used in β cells to regulate Ca2+ influx for insulin secretion. β cell-specific ELKS-knockout (KO) mice showed impaired glucose-stimulated first-phase insulin secretion and reduced L-type voltage-dependent Ca2+ channel (VDCC) current density. In situ Ca2+ imaging of β cells within islets expressing a membrane-bound G-CaMP8b Ca2+ sensor demonstrated initial local Ca2+ signals at the ELKS-localized vascular side of the β cell plasma membrane, which were markedly decreased in ELKS-KO β cells. Mechanistically, ELKS directly interacted with the VDCC-β subunit via the GK domain. These findings suggest that ELKS and VDCCs form a potent insulin secretion complex at the vascular side of the β cell plasma membrane for polarized Ca2+ influx and first-phase insulin secretion from pancreatic islets.",
keywords = "Ca influx, ELKS, active zone protein, insulin exocytosis, pancreatic β cells, voltage-dependent Ca channel",
author = "Mica Ohara-Imaizumi and Kyota Aoyagi and Hajime Yamauchi and Masashi Yoshida and Mori, {Masayuki X.} and Yamato Hida and Tran, {Ha Nam} and Masamichi Ohkura and Manabu Abe and Yoshihiro Akimoto and Yoko Nakamichi and Chiyono Nishiwaki and Hayato Kawakami and Kazuo Hara and Kenji Sakimura and Shinya Nagamatsu and Yasuo Mori and Junichi Nakai and Masafumi Kakei and Toshihisa Ohtsuka",
note = "Funding Information: This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI ( 26460396 and 17K08547 to M.O.-I., 17K09845 to K.A., 16K19545 to M.Y., 15H05723 and 16H06536 to J.N., and 15H04272 to T.O.), Japan diabetes foundation (to M.O.-I.), Kyorin University School of Medicine Joint research program (to M.O.-I.), Gunma University Joint research program ( 15010 to K.A.), JST CREST Grant Number JPMJCR1751 , Japan (to T.O.), the program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from MEXT , the Japan Agency for Medical Research and Development (AMED) (to J.N.), Junior Scientist Development Grant supported by Novo Nordisk Pharma (to K.A.), Takeda Science Foundation (to K.A.), and the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan (to M.O.-I. and S.N.). We thank Ms. Sachie Matsubara and Ms. Junri Sekiguchi (Laboratory for Electron Microscopy, Kyorin University School of Medicine) for technical assistance with electron microscopy. Funding Information: This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI (26460396 and 17K08547 to M.O.-I., 17K09845 to K.A., 16K19545 to M.Y., 15H05723 and 16H06536 to J.N., and 15H04272 to T.O.), Japan diabetes foundation (to M.O.-I.), Kyorin University School of Medicine Joint research program (to M.O.-I.), Gunma University Joint research program (15010 to K.A.), JST CREST Grant Number JPMJCR1751, Japan (to T.O.), the program for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from MEXT, the Japan Agency for Medical Research and Development (AMED) (to J.N.), Junior Scientist Development Grant supported by Novo Nordisk Pharma (to K.A.), Takeda Science Foundation (to K.A.), and the Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan (to M.O.-I. and S.N.). We thank Ms. Sachie Matsubara and Ms. Junri Sekiguchi (Laboratory for Electron Microscopy, Kyorin University School of Medicine) for technical assistance with electron microscopy. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = jan,
day = "29",
doi = "10.1016/j.celrep.2018.12.106",
language = "English",
volume = "26",
pages = "1213--1226.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}