Research ArticleIon Channels

TALK-1 channels control β cell endoplasmic reticulum Ca2+ homeostasis

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Science Signaling  19 Sep 2017:
Vol. 10, Issue 497, eaan2883
DOI: 10.1126/scisignal.aan2883

TALKing about K+, Ca2+, and ER stress

Insulin secretion is triggered upon depolarization of β cells, which activates voltage-gated Ca2+ channels in the plasma membrane. Ca2+ that enters the β cells is taken up by the endoplasmic reticulum (ER) and released near Ca2+-activated K+ channels in the plasma membrane that repolarize β cells. Vierra et al. showed that TALK-1 channels provided the K+ influx into the ER that counterbalanced Ca2+ release from the ER in mouse and human β cells. ER Ca2+ content is reduced in diabetic β cells, which can result in ER stress and further accentuate β cell dysfunction. The authors found that mRNA markers of ER stress were decreased in islets from TALK-1 knockout mice fed a high-fat diet and suggest that targeting TALK-1 activity may suppress ER stress and improve β cell ER Ca2+ handling in diabetes.


Ca2+ handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic β 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 β cells. We found that β 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 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 Ca2+ and suggest that TALK-1 may be a therapeutic target to reduce ER Ca2+ handling defects in β cells during the pathogenesis of diabetes.

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