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TALK-1 channels control ß cell endoplasmic reticulum Ca(2+) homeostasis.

Authors	Vierra NC, Dadi PK, Milian SC, Dickerson MT, Jordan KL, Gilon P, Jacobson DA
Submitted By	Submitted Externally on 11/9/2017
Status	Published
Journal	Science signaling
Year	2017
Date Published	9/1/2017
Volume : Pages	10 : Not Specified
PubMed Reference	28928238
Abstract	Ca(2+) handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic ß cell function and becomes perturbed during the pathogenesis of diabetes. ER Ca(2+) 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(2+) release from the ER in mouse and human ß cells. We found that ß cells from mice lacking TALK-1 exhibited reduced basal cytosolic Ca(2+) and increased ER Ca(2+) concentrations, suggesting reduced ER Ca(2+) leak. These changes in Ca(2+) 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(2+) stores. Reduced ER Ca(2+) content in ß 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 ß cell ER Ca(2+) and suggest that TALK-1 may be a therapeutic target to reduce ER Ca(2+) handling defects in ß cells during the pathogenesis of diabetes.

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