TALK-1 channels control β cell endoplasmic reticulum Ca homeostasis.

Vierra NC, Dadi PK, Milian SC, Dickerson MT, Jordan KL, Gilon P, Jacobson DA
Sci Signal. 2017 10 (497)

PMID: 28928238 · PMCID: PMC5672804 · DOI:10.1126/scisignal.aan2883

Ca handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic β cell function and becomes perturbed during the pathogenesis of diabetes. ER Ca homeostasis is determined by ion movements across the ER membrane, including K flux through K channels. We demonstrated that K flux through ER-localized TALK-1 channels facilitated Ca release from the ER in mouse and human β cells. We found that β cells from mice lacking TALK-1 exhibited reduced basal cytosolic Ca and increased ER Ca concentrations, suggesting reduced ER Ca leak. These changes in Ca homeostasis were presumably due to TALK-1-mediated ER K flux, because we recorded K currents mediated by functional TALK-1 channels on the nuclear membrane, which is continuous with the ER. Moreover, overexpression of K-impermeable TALK-1 channels in HEK293 cells did not reduce ER Ca stores. Reduced ER Ca content in β cells is associated with ER stress and islet dysfunction in diabetes, and islets from TALK-1-deficient mice fed a high-fat diet showed reduced signs of ER stress, suggesting that TALK-1 activity exacerbated ER stress. Our data establish TALK-1 channels as key regulators of β cell ER Ca and suggest that TALK-1 may be a therapeutic target to reduce ER Ca handling defects in β cells during the pathogenesis of diabetes.

Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

MeSH Terms (11)

Animals Calcium Diabetes Mellitus Endoplasmic Reticulum HEK293 Cells Homeostasis Humans Insulin-Secreting Cells Mice Mice, Knockout Potassium Channels, Tandem Pore Domain

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