Insulin secretion by pancreatic β-cells occurs in response to glucose-induced increases in intracellular calcium (Ca2+c). Past research has shown that fluxes in Ca2+ from the endoplasmic reticulum (ER) play a role in this process, and that these fluxes can be disturbed in diabetes. The movement of Ca2+ across the ER membrane is electrically balanced by an opposing movement of K+; however, the identity of the K+ channel responsible for this movement has remained a mystery. Now, Vanderbilt Basic Sciences investigator David Jacobson and his laboratory identify the TALK-1 K+ channel as a key player in β-cell Ca2+ homeostasis. The investigators first confirmed that TALK-1 is expressed in the ER membrane of both mouse and human β-cells, and they used β-cells from TALK-1 knockout (KO) mice to show that TALK-1 decreases the amount of Ca2+ stored in the ER (Ca2+ER) while raising basal Ca2+c. These findings suggested that TALK-1 promotes leakage of Ca2+ER, and results from overexpression of the related K+ channels TASK-1 and TASK-3 in HEK293 cells indicated that they perform the same function. In fact, inhibition of TASK-1 expressed in pancreatic α-cells using a specific channel blocker reduced Ca2+ER leakage in those cells. Electrophysiology experiments confirmed that TALK-1 and TASK-1 form functional K+ channels in β- and α-cells, respectively, and they showed that Ca2+ER release is reduced in TALK-1 β-cells responding to a depolarizing stimulus. However, exposure of TALK-1 KO cells to high glucose resulted in higher Ca2+ influx and more radical Ca2+ oscillations. The investigators explained this observation by hypothesizing that release of Ca2+ER is required to stimulate a plasma membrane-based slow K+ current that dampens the oscillations. A failure of normal Ca2+ER homeostasis can lead to ER stress. The investigators found that islets from TALK-1 KO mice exhibited decreased expression of ER stress response genes in response to prolonged exposure to a high fat diet. Furthermore, cells expressing a type 2 diabetes-linked gain-of-function TALK-1 mutant showed an increased ER stress response to tunicamycin exposure. The results suggest that TALK-1 is directly related to insulin secretion and maintenance of ER homeostasis. Thus, it may be a target for drug discovery to treat inappropriate Ca2+ER release during diabetes pathogenesis. The work is published in the journal Science Signaling [N. C. Vierra, et al., (2017) Sci. Signal. 10, eaan2883].
Figure reproduced with permission from N. C. Vierra, et al., (2017) Sci. Signal. 10, eaan2883. Copyright 2017 AAAS.