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- W2585854140 abstract "The two-pore domain K+ (K2P) channel TALK-1 modulates insulin secretion by limiting β-cell electrical excitability and cytosolic Ca2+ (Ca2+c) influx. Mouse islets lacking TALK-1 (KO) exhibit accelerated Ca2+c oscillations and enhanced insulin secretion relative to controls (WT). The Ca2+c oscillation frequency is affected by Kslow, a repolarizing Ca2+-dependent K+ current. Kslow is reduced in KO β-cells, possibly contributing to the accelerated Ca2+c oscillations of KO islets. Since TALK-1 activity is not regulated by Ca2+c, we assessed whether TALK-1 impacts Ca2+ release from endoplasmic reticulum (ER) stores (Ca2+ER), which modulates Kslow. We find lower basal Ca2+c in KO β-cells, and application of the SERCA inhibitor CPA causes a greater increase in Ca2+c in KO versus WT β-cells. These observations suggest that TALK-1 regulates Ca2+ER. Therefore, we tested how heterologous expression of TALK-1 in HEK293 cells affects Ca2+ER. TALK-1 overexpression significantly increases basal Ca2+c and reduces the CPA-induced Ca2+c response. However, expression of the K2P channels TREK-1 or TREK-2 does not affect Ca2+ER. Furthermore, K+-impermeable mutant TALK-1 channels do not recapitulate Ca2+ER defects, thus, TALK-1 K+ channel function presumably modulates Ca2+ER. Consistent with an intracellular role for TALK-1, fluorescence microscopy reveals expression of TALK-1 in the β-cell ER. Additionally, nuclear patch-clamp experiments demonstrate the presence of functional TALK-1 channels on the outer nuclear membrane, which is continuous with the ER. Moreover, specific inhibition of endogenous TALK-1 channels with expression of a K+-impermeable mutant increased human β-cell Ca2+ER. Together, our data suggest that TALK-1 channel activity augments islet-cell Ca2+ER “leak.” Altered TALK-1 channel function may perturb islet-cell Ca2+ER, which can affect Ca2+c handling, hormone release, and contribute to disease pathogenesis." @default.
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- W2585854140 date "2017-02-01" @default.
- W2585854140 modified "2023-09-28" @default.
- W2585854140 title "The Two-Pore Domain K + Channel TALK-1 Provides a Countercurrent that Facilitates Endoplasmic Reticulum Ca 2+ Leak" @default.
- W2585854140 doi "https://doi.org/10.1016/j.bpj.2016.11.2622" @default.
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