| First Author | Vierra NC | Year | 2017 |
| Journal | Sci Signal | Volume | 10 |
| Issue | 497 | PubMed ID | 28928238 |
| Mgi Jnum | J:259519 | Mgi Id | MGI:6141934 |
| Doi | 10.1126/scisignal.aan2883 | Citation | Vierra NC, et al. (2017) TALK-1 channels control beta cell endoplasmic reticulum Ca(2+) homeostasis. Sci Signal 10(497) |
| abstractText | Ca(2+) handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic beta 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 beta cells. We found that beta 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 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 Ca(2+) and suggest that TALK-1 may be a therapeutic target to reduce ER Ca(2+) handling defects in beta cells during the pathogenesis of diabetes. |
