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

Vierra, Nicholas C.; Dickerson, Matthew; Jordan, Kelli L.; Dadi, Prasanna K.; Katdare, Ketaki A.; Altman, Molly K.; Milian, Sarah C.; Jacobson, David A.

doi:10.1016/j.molmet.2018.01.016

Cited by 26 publications

(27 citation statements)

References 72 publications

(128 reference statements)

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“…How does cAMP mediate the V m -independent effect on somatostatin secretion? Accumulating evidence indicates that Ca 2+ release from the ER represents a key signal for somatostatin secretion ( Zhang et al, 2007 ; Li et al, 2017 ; Vierra et al, 2018 ). The cAMP-mediated amplifying effect of glucose on somatostatin secretion is likely to be exerted, at least partially, by augmenting ER Ca 2+ release in δ-cells.…”

Section: Discussionmentioning

confidence: 99%

Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release

Denwood

Tarasov

Salehi

et al. 2019

Journal of General Physiology

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Somatostatin secretion from pancreatic islet δ-cells is stimulated by elevated glucose levels, but the underlying mechanisms have only partially been elucidated. Here we show that glucose-induced somatostatin secretion (GISS) involves both membrane potential-dependent and -independent pathways. Although glucose-induced electrical activity triggers somatostatin release, the sugar also stimulates GISS via a cAMP-dependent stimulation of CICR and exocytosis of somatostatin. The latter effect is more quantitatively important and in mouse islets depolarized by 70 mM extracellular K+, increasing glucose from 1 mM to 20 mM produced an ∼3.5-fold stimulation of somatostatin secretion, an effect that was mimicked by the application of the adenylyl cyclase activator forskolin. Inhibiting cAMP-dependent pathways with PKI or ESI-05, which inhibit PKA and exchange protein directly activated by cAMP 2 (Epac2), respectively, reduced glucose/forskolin-induced somatostatin secretion. Ryanodine produced a similar effect that was not additive to that of the PKA or Epac2 inhibitors. Intracellular application of cAMP produced a concentration-dependent stimulation of somatostatin exocytosis and elevation of cytoplasmic Ca2+ ([Ca2+]i). Both effects were inhibited by ESI-05 and thapsigargin (an inhibitor of SERCA). By contrast, inhibition of PKA suppressed δ-cell exocytosis without affecting [Ca2+]i. Simultaneous recordings of electrical activity and [Ca2+]i in δ-cells expressing the genetically encoded Ca2+ indicator GCaMP3 revealed that the majority of glucose-induced [Ca2+]i spikes did not correlate with δ-cell electrical activity but instead reflected Ca2+ release from the ER. These spontaneous [Ca2+]i spikes are resistant to PKI but sensitive to ESI-05 or thapsigargin. We propose that cAMP links an increase in plasma glucose to stimulation of somatostatin secretion by promoting CICR, thus evoking exocytosis of somatostatin-containing secretory vesicles in the δ-cell.

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Section: Discussionmentioning

confidence: 99%

Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release

Denwood

Tarasov

Salehi

et al. 2019

Journal of General Physiology

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“…014538; The Jackson Laboratory) [ 39 ]. Similarly, transgenic mice expressing GCaMP6s, specifically in δ-cells, were generated by crossing Sst-IRES-Cre mice (Stock No: 013044; The Jackson Laborator) with mice possessing the genetically encoded Ca 2+ indicator GCaMP6s preceded by a loxP-flanked STOP cassette (Stock No: 028866; The Jackson Laborato) [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

Lactate activation of α-cell KATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca2+ entry

Zaborska

Dadi

Dickerson

et al. 2020

Molecular Metabolism

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Objective Elevations in pancreatic α-cell intracellular Ca 2+ ([Ca 2+ ] i ) lead to glucagon (GCG) secretion. Although glucose inhibits GCG secretion, how lactate and pyruvate control α-cell Ca 2+ handling is unknown. Lactate enters cells through monocarboxylate transporters (MCTs) and is also produced during glycolysis by lactate dehydrogenase A (LDHA), an enzyme expressed in α-cells. As lactate activates ATP-sensitive K + (K ATP ) channels in cardiomyocytes, lactate may also modulate α-cell K ATP . Therefore, this study investigated how lactate signaling controls α-cell Ca 2+ handling and GCG secretion. Methods Mouse and human islets were used in combination with confocal microscopy, electrophysiology, GCG immunoassays, and fluorescent thallium flux assays to assess α-cell Ca 2+ handling, V m , K ATP currents, and GCG secretion. Results Lactate-inhibited mouse (75 ± 25%) and human (47 ± 9%) α-cell [Ca 2+ ] i fluctuations only under low-glucose conditions (1 mM) but had no effect on β- or δ-cells [Ca 2+ ] i . Glyburide inhibition of K ATP channels restored α-cell [Ca 2+ ] i fluctuations in the presence of lactate. Lactate transport into α-cells via MCTs hyperpolarized mouse (14 ± 1 mV) and human (12 ± 1 mV) α-cell V m and activated K ATP channels. Interestingly, pyruvate showed a similar K ATP activation profile and α-cell [Ca 2+ ] i inhibition as lactate. Lactate-induced inhibition of α-cell [Ca 2+ ] i influx resulted in reduced GCG secretion in mouse (62 ± 6%) and human (43 ± 13%) islets. Conclusions These data demonstrate for the first time that lactate entry into α-cells through MCTs results in K ATP activation, V m hyperpolarization, reduced [Ca 2+ ] i , and inhibition of GCG secretion. Thus, taken together, these data indicate that lactate either within α-cells and/or elevated in serum could serve as important modulators of α-cell function.

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“…Leu114Pro may contribute to β-cell dysfunction via ER-stress, as observed in some MODY subtypes (e.g., INS mutations in MODY-10 35 ); however, this remains speculative. Additionally, although highly -cell specific, TALK-1 is also expressed in human pancreatic δ-cells where it negatively regulates somatostatin release 36 . TALK-1 KO mice show increased somatostatin secretion under low and high glucose conditions, due to enhanced Ca 2+ ER release 36 ; thus, a gain-of-function mutation in TALK-1 may reduce δ-cell somatostatin secretion.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, although highly -cell specific, TALK-1 is also expressed in human pancreatic δ-cells where it negatively regulates somatostatin release 36 . TALK-1 KO mice show increased somatostatin secretion under low and high glucose conditions, due to enhanced Ca 2+ ER release 36 ; thus, a gain-of-function mutation in TALK-1 may reduce δ-cell somatostatin secretion. The glycemic effects of this would be complex given the inhibitory effect of somatostatin on both insulin and glucagon secretion 36 ; and require future investigation.…”

Section: Discussionmentioning

confidence: 99%

“…TALK-1 KO mice show increased somatostatin secretion under low and high glucose conditions, due to enhanced Ca 2+ ER release 36 ; thus, a gain-of-function mutation in TALK-1 may reduce δ-cell somatostatin secretion. The glycemic effects of this would be complex given the inhibitory effect of somatostatin on both insulin and glucagon secretion 36 ; and require future investigation. Some MODY subtypes (e.g., ABCC8-, KCNJ11-, HNF1-and HNF4 MODY) are manageable through KATP inhibition 7,37,38 -i.e., sulfonylurea use.…”

Section: Discussionmentioning

confidence: 99%

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A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young

Graff

Johnson

Leo

et al. 2020

Preprint

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Word count2820 3 ABSTRACT Background Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired glucose-stimulated insulin secretion (GSIS). Mechanisms include β-cell KATP channel dysfunction (e.g., KCNJ11 (MODY13) or ABCC8 (MODY12) mutations); however, no other β-cell channelopathies have been identified in MODY. MethodsA four-generation family with autosomal dominant non-obese, non-ketotic antibody-negative diabetes, without mutations in known MODY genes, underwent exome sequencing. Whole-cell and single-channel K + currents, Ca 2+ handling, and GSIS were determined in cells expressing either mutated or wild-type (WT) protein. ResultsWe identified a novel non-synonymous genetic mutation in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and -cell-restricted K + channel transcript and encodes the two-pore-domain K + channel TALK-1. Whole-cell K + currents in transfected HEK293 cells demonstrated drastic (312-fold increase) gain-of-function with TALK-1 Leu144Pro vs. WT, due to greater single channel activity. Glucose-stimulated cytosolic Ca 2+ influx was inhibited in mouse islets expressing TALK-1 Leu114Pro (area under the curve [AUC] at 20mM glucose: Leu114Pro 60.1 vs. WT 89.1; P=0.030) and less endoplasmic reticulum calcium storage (cyclopiazonic acid-induced release AUC:Leu114Pro 17.5 vs. WT 46.8; P=0.008). TALK-1 Leu114Pro significantly blunted GSIS compared to TALK-1 WT in both mouse (52% decrease, P=0.039) and human (38% decrease, P=0.019) islets.

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

Cited by 26 publications

References 72 publications

Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release

Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release

Lactate activation of α-cell KATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca2+ entry

A novel mutation inKCNK16causing a gain-of-function in the TALK-1 potassium channel: a new cause of maturity onset diabetes of the young

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