Potassium channel subfamily K member 16
potassium channel activity
TALK-1 channels control β cell endoplasmic reticulum Ca<sup>2+</sup> homeostasis.
Ca<sup>2+</sup> 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<sup>2+</sup> homeostasis is determined by ion movements across the ER membrane, including K<sup>+</sup> flux through K<sup>+</sup> channels. We demonstrated that K<sup>+</sup> flux through ER-localized TALK-1 channels facilitated Ca<sup>2+</sup> 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<sup>2+</sup> and increased ER Ca<sup>2+</sup> concentrations, suggesting reduced ER Ca<sup>2+</sup> leak. These changes in Ca<sup>2+</sup> homeostasis were presumably due to TALK-1-mediated ER K<sup>+</sup> flux, because we recorded K<sup>+</sup> currents mediated by functional TALK-1 channels on the nuclear membrane, which is continuous with the ER. Moreover, overexpression of K<sup>+</sup>-impermeable TALK-1 channels in HEK293 cells did not reduce ER Ca<sup>2+</sup> stores. Reduced ER Ca<sup>2+</sup> 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<sup>2+</sup> and suggest that TALK-1 may be a therapeutic target to reduce ER Ca<sup>2+</sup> handling defects in β cells during the pathogenesis of diabetes.