• Vierra NC, Dadi PK, Milian SC, Dickerson MT, Jordan KL, Gilon P, Jacobson DA. TALK-1 channels control β cell endoplasmic reticulum Ca(2+) homeostasis. Science signaling. 2017 Sep 19;10(497). PMID: 28928238 [PubMed].

Abstract 

Ca(2+) 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(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 β cells. We found that β 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 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(2+) and suggest that TALK-1 may be a therapeutic target to reduce ER Ca(2+) handling defects in β cells during the pathogenesis of diabetes.