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

Autor:	Vierra NC; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Dickerson MT; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Jordan KL; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Dadi PK; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Katdare KA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Altman MK; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Milian SC; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Jacobson DA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: david.a.jacobson@vanderbilt.edu.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2018 Mar; Vol. 9, pp. 84-97. Date of Electronic Publication: 2018 Jan 31.
DOI:	10.1016/j.molmet.2018.01.016
Abstrakt:	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 ²⁺ leak, modulating Ca ²⁺ handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca ²⁺ -induced Ca ²⁺ release (CICR) from the δ-cell ER, we investigated whether TALK-1 modulates δ-cell Ca ²⁺ 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 ²⁺ 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 ²⁺ and somatostatin secretion. Measurement of cytosolic Ca ²⁺ levels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO δ-cells that could be abolished by depleting ER Ca ²⁺ with sarco/endoplasmic reticulum Ca ²⁺ ATPase (SERCA) inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and α-cell Ca ²⁺ 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 ²⁺ 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.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu