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

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.