期刊
SCIENCE SIGNALING
卷 10, 期 497, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aan2883
关键词
-
资金
- NIH [K01DK081666, R01DK097392, 1F31DK109625]
- Vanderbilt Diabetes Research and Training Center Pilot and Feasibility [P60DK20593]
- American Diabetes Association [1-17-IBS-024]
- Vanderbilt Molecular Endocrinology Training Program (METP) [5T32DK07563]
- Vanderbilt METP [5T32DK007563-28]
- Vanderbilt Integrated Training in Engineering and Diabetes [T32DK101003]
Ca2+ handling by the endoplasmic reticulum ( ER) serves critical roles in controlling pancreatic beta cell function and becomes perturbed during the pathogenesis of diabetes. ER Ca2+ 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 Ca2+ release from the ER in mouse and human beta cells. We found that beta cells from mice lacking TALK-1 exhibited reduced basal cytosolic Ca2+ and increased ER Ca2+ concentrations, suggesting reduced ER Ca2+ leak. These changes in Ca2+ 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 Ca2+ stores. Reduced ER Ca2+ content in beta 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 beta cell ER Ca2+ and suggest that TALK-1 may be a therapeutic target to reduce ER Ca2+ handling defects in beta cells during the pathogenesis of diabetes.
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