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TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels
limiting somatostatin secretion.
Authors Vierra NC, Dickerson MT, Jordan KL, Dadi PK, Kadare KA, Altman MK, Milian SC,
Jacobson DA
Submitted By Submitted Externally on 4/9/2018
Status Published
Journal Molecular metabolism
Year 2018
Date Published 3/1/2018
Volume : Pages 9 : 84 - 97
PubMed Reference 29402588
Abstract 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 d-cells. However, a physiological role for TALK-1 in
d-cells remains unknown. We previously determined that in ß-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 d-cell ER, we investigated whether TALK-1 modulates d-cell
Ca2+handling and somatostatin secretion., To define the functions of islet
d-cell TALK-1 channels, we generated control and TALK-1 channel-deficient
(TALK-1 KO) mice expressing fluorescent reporters specifically in d- and a-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 d- and a-cell function., TALK-1 channels are
expressed in both mouse and human d-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 d-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 a-cell Ca2+oscillations in
TALK-1 KO islets, and found that blockade of a-cell somatostatin signaling with
a somatostatin receptor 2 (SSTR2) antagonist restored glucagon secretion in
TALK-1 KO islets., These data indicate that TALK-1 reduces d-cell cytosolic
Ca2+elevations and somatostatin release by limiting d-cell CICR, modulating the
intraislet paracrine signaling mechanisms that control glucagon secretion.


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