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, Kflux through endoplasmic reticulum (ER)-localized TALK-1 channels enhances ER Caleak, modulating Cahandling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca-induced Carelease (CICR) from the δ-cell ER, we investigated whether TALK-1 modulates δ-cell Cahandling 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, Caimaging, 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 Caand somatostatin secretion. Measurement of cytosolic Calevels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO δ-cells that could be abolished by depleting ER Cawith sarco/endoplasmic reticulum CaATPase (SERCA) inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and α-cell Caoscillations 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 Caelevations 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.