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TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels
limiting somatostatin secretion.
Vierra NC, Dickerson MT, Jordan KL, Dadi PK, Kadare KA, Altman MK, Milian SC,
Submitted Externally on 4/9/2018
Volume : Pages
9 : 84 - 97
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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