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

ABSTRACT: 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 ?-cells. However, a physiological role for TALK-1 in ?-cells remains unknown. We previously determined that in ?-cells, K+ flux through endoplasmic reticulum (ER)-localized TALK-1 channels enhances ER Ca2+ leak, modulating Ca2+ handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca2+-induced Ca2+ release (CICR) from the ?-cell ER, we investigated whether TALK-1 modulates ?-cell Ca2+ handling and somatostatin secretion. METHODS:To define the functions of islet ?-cell TALK-1 channels, we generated control and TALK-1 channel-deficient (TALK-1 KO) mice expressing fluorescent reporters specifically in ?- and ?-cells to facilitate cell type identification. Using immunofluorescence, patch clamp electrophysiology, Ca2+ imaging, and hormone secretion assays, we assessed how TALK-1 channel activity impacts ?- and ?-cell function. RESULTS:TALK-1 channels are expressed in both mouse and human ?-cells, where they modulate glucose-stimulated changes in cytosolic Ca2+ and somatostatin secretion. Measurement of cytosolic Ca2+ levels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO ?-cells that could be abolished by depleting ER Ca2+ with sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and ?-cell Ca2+ oscillations in TALK-1 KO islets, and found that blockade of ?-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 ?-cell cytosolic Ca2+ elevations and somatostatin release by limiting ?-cell CICR, modulating the intraislet paracrine signaling mechanisms that control glucagon secretion.

SUBMITTER: Vierra NC 

PROVIDER: S-EPMC5870147 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature