TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion.

Vierra NC, Dickerson MT, Jordan KL, Dadi PK, Katdare KA, Altman MK, Milian SC, Jacobson DA
Mol Metab. 2018 9: 84-97

PMID: 29402588 · PMCID: PMC5870147 · DOI:10.1016/j.molmet.2018.01.016

OBJECTIVE - Single-cell RNA sequencing studies have revealed that the type-2 diabetes associated two-pore domain K (K2P) channel TALK-1 is abundantly expressed in somatostatin-secreting δ-cells. However, a physiological role for TALK-1 in δ-cells remains unknown. We previously determined that in β-cells, K flux through endoplasmic reticulum (ER)-localized TALK-1 channels enhances ER Ca leak, modulating Ca handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca-induced Ca release (CICR) from the δ-cell ER, we investigated whether TALK-1 modulates δ-cell Ca handling and somatostatin secretion.

METHODS - To define the functions of islet δ-cell TALK-1 channels, we generated control and TALK-1 channel-deficient (TALK-1 KO) mice expressing fluorescent reporters specifically in δ- and α-cells to facilitate cell type identification. Using immunofluorescence, patch clamp electrophysiology, Ca imaging, and hormone secretion assays, we assessed how TALK-1 channel activity impacts δ- and α-cell function.

RESULTS - TALK-1 channels are expressed in both mouse and human δ-cells, where they modulate glucose-stimulated changes in cytosolic Ca and somatostatin secretion. Measurement of cytosolic Ca levels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO δ-cells that could be abolished by depleting ER Ca with sarco/endoplasmic reticulum Ca ATPase (SERCA) inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and α-cell Ca oscillations in TALK-1 KO islets, and found that blockade of α-cell somatostatin signaling with a somatostatin receptor 2 (SSTR2) antagonist restored glucagon secretion in TALK-1 KO islets.

CONCLUSIONS - These data indicate that TALK-1 reduces δ-cell cytosolic Ca elevations and somatostatin release by limiting δ-cell CICR, modulating the intraislet paracrine signaling mechanisms that control glucagon secretion.

Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.

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