ELKS/Voltage-Dependent Ca 2+ Channel-β Subunit Module Regulates Polarized Ca 2+ Influx in Pancreatic β Cells

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / drug effects
  • Blood Vessels / metabolism
  • Calcium / metabolism*
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin Secretion / drug effects
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Ion Channel Gating / drug effects
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Nerve Tissue Proteins / deficiency
  • Nerve Tissue Proteins / metabolism*
  • Protein Binding / drug effects
  • Protein Subunits / metabolism*
  • rab GTP-Binding Proteins / deficiency
  • rab GTP-Binding Proteins / metabolism*

Substances

  • Erc1 protein, mouse
  • Insulin
  • Nerve Tissue Proteins
  • Protein Subunits
  • rab GTP-Binding Proteins
  • Glucose
  • Calcium