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Cell Rep. 2019 Jan 29;26(5):1213-1226.e7. doi: 10.1016/j.celrep.2018.12.106.

ELKS/Voltage-Dependent Ca2+ Channel-β Subunit Module Regulates Polarized Ca2+ Influx in Pancreatic β Cells.

Author information

1
Department of Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan. Electronic address: mimaizu@ks.kyorin-u.ac.jp.
2
Department of Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
3
Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan.
4
First Department of Medicine, Saitama Medical Center, Jichi Medical University School of Medicine, Saitama 337-8503, Japan.
5
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
6
Department of Technology and Ecology, Hall of Global Environmental Studies, Kyoto University, Kyoto 615-8510, Japan.
7
Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan; Brain and Body System Science Institute, Saitama University, Saitama 338-8570, Japan.
8
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
9
Department of Anatomy, Kyorin University School of Medicine, Tokyo 181-8611, Japan.
10
Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
11
Department of Biochemistry, Kyorin University School of Medicine, Tokyo 181-8611, Japan; Shinei-Diabetic-Clinic, Tokyo 166-0003, Japan.
12
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan; Department of Technology and Ecology, Hall of Global Environmental Studies, Kyoto University, Kyoto 615-8510, Japan.
13
Department of Biochemistry, Graduate School of Medicine, University of Yamanashi, Yamanashi 409-3898, Japan. Electronic address: tohtsuka@yamanashi.ac.jp.

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(2+) influx; ELKS; active zone protein; insulin exocytosis; pancreatic β cells; voltage-dependent Ca(2+) channel

PMID:
30699350
DOI:
10.1016/j.celrep.2018.12.106
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