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.

MeSH Terms (13)

Animals Calcium Signaling Cells, Cultured Cytoplasm Endoplasmic Reticulum Glucagon Humans Male Mice Mice, Inbred C57BL Potassium Channels, Tandem Pore Domain Somatostatin Somatostatin-Secreting Cells

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