ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion

Rorsman, Patrik; Ramracheya, Reshma; Rorsman, Nils J.G.; Zhang, Quan

doi:10.1007/s00125-014-3279-8

Cited by 81 publications

(88 citation statements)

References 84 publications

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“…The lower density of K ATP currents in the αRaptor HET α cells is therefore consistent with the suppressive effect of tolbutamide on glucagon secretion occurring at low glucose concentrations, and the lack of effect of diazoxide. Interestingly, the increase in glucagon secretion by diazoxide in control islets is opposite to previously published data showing that a similar concentration of diazoxide inhibits, rather than stimulates glucagon secretion (33). The mechanisms for these differences are not completely clear but it is important to note that a fraction of K ATP channels in α cells are open even at low glucose (23,34).…”

Section: +contrasting

confidence: 68%

“…In contrast, glucagon responses to arginine, glutamine, or tolbutamide were impaired in αRaptor HET ( Figure 6, B and C, and Supplemental Figure 5). While tolbutamide and arginine should also depolarize the α cell, KCl likely provided a much stronger depolarization that supports the sustained activation of L-type Ca 2+ channels, as opposed to the P/Q-type channels that appear to control glucagon secretion under more physiologic conditions (33,34). Based on these findings, together with impaired responses to low glucose observed in vivo, we hypothesized that the mechanistic defect in the glucagon secretory pathways in αRaptor HET lied at the level of the K ATP channel.…”

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confidence: 98%

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Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Bozadjieva¹,

Blandino-Rosano²,

Chase³

et al. 2017

Journal of Clinical Investigation

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Glucagon plays a major role in the regulation of glucose homeostasis during fed and fasting states. However, the mechanisms responsible for the regulation of pancreatic α cell mass and function are not completely understood. In the current study, we identified mTOR complex 1 (mTORC1) as a major regulator of α cell mass and glucagon secretion. Using mice with tissuespecific deletion of the mTORC1 regulator Raptor in α cells (αRaptor KO ), we showed that mTORC1 signaling is dispensable for α cell development, but essential for α cell maturation during the transition from a milk-based diet to a chow-based diet after weaning. Moreover, inhibition of mTORC1 signaling in αRaptor KO mice and in WT animals exposed to chronic rapamycin administration decreased glucagon content and glucagon secretion. In αRaptor KO mice, impaired glucagon secretion occurred in response to different secretagogues and was mediated by alterations in K ATP channel subunit expression and activity. Additionally, our data identify the mTORC1/FoxA2 axis as a link between mTORC1 and transcriptional regulation of key genes responsible for α cell function. Thus, our results reveal a potential function of mTORC1 in nutrient-dependent regulation of glucagon secretion and identify a role for mTORC1 in controlling α cell-mass maintenance.Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 3 8 0 jci.org Volume 127 Number 12 December 2017 transcription of critical α cell genes. This work provides insights into how nutrient-dependent glucagon secretion and α cell mass are regulated and suggest that pharmacologic inhibition of this pathway using immunosuppressant medications, such as everolimus or rapamycin, could alter glucagon levels and glucose homeostasis. ResultsLack of mTORC1 signaling after deletion of Raptor in α cells. α Cell-specific deletion of Raptor was achieved by crossing glucagon-Cre and Raptor fl/fl mice (αRaptor KO ) (18,19). Deletion of flanked exon 6 exclusively in α cells from αRaptor KO mice was demonstrated by nested reverse transcription PCR (RT-PCR) for exon 6 using different tissues and single α cells ( Figure 1A) (19). Loss of mTORC1 signaling was confirmed by lack of phospho-S6 (Ser240) immunofluorescence staining only in glucagon-positive cells in dispersed islets from 1-month-old αRaptor KO mice ( Figure 1B). To validate the reduction in mTORC1 signaling in α cells from αRaptor KO mice, we assessed phospho-S6 (Ser240), glucagon, and insulin staining in dispersed islets by flow cytometry using quantitative mean fluorescence intensity (MFI). Figure 1C shows pS6 MFI levels in α cells (glucagon + cell count) and Figure 1D includes pS6 MFI levels in β cells (insulin + cell count). Phospho-S6 (Ser240) levels were nearly lost in glucagon-positive cells from αRaptor KO mice (red curve) compared with controls (black curve) (Figures 1C). In contrast, the MFI for phospho-S6 (Se240) was similar in insulin-positive cells from αRaptor ...

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Section: +contrasting

confidence: 68%

mentioning

confidence: 98%

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Bozadjieva¹,

Blandino-Rosano²,

Chase³

et al. 2017

Journal of Clinical Investigation

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“…The mechanism of the loss of glucagon response is poorly understood, but recent evidence suggests that it could be related to the increased activity of adenosine triphosphateeregulated potassium channels in glucagon-producing a cells. 40 The pathogenesis of impaired catecholamine and other hormone responses is also not entirely clear but may have been set in motion from recurrent hypoglycemia that (1) impairs glucose sensing in the ventromedial hypothalamus (a brain region that plays a major role in controlling the counterregulatory responses to hypoglycemia) and (2) leads to cellular adaptation that results in hypoglycemia unawareness and reduced adrenomedullary response to subsequent hypoglycemia. 41,42 Defective glucose counterregulation plays a major role in the susceptibility to severe hypoglycemia in patients with type 1 diabetes.…”

Section: Hypoglycemia Counterregulationmentioning

confidence: 99%

Hypoglycemia, Chronic Kidney Disease, and Diabetes Mellitus

Alsahli

Gerich

2014

Mayo Clinic Proceedings

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Hypoglycemia is a major problem associated with substantial morbidity and mortality in patients with diabetes and is often a major barrier to achieving optimal glycemic control. Chronic kidney disease not only is an independent risk factor for hypoglycemia but also augments the risk of hypoglycemia that is already present in people with diabetes. This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetes and chronic kidney disease and reviews therapeutic considerations in this situation. PubMed and MEDLINE were searched

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“…Although multiple past studies focused on understanding the implications of ATP-controlled signaling with respect to endogenous transmembrane transporters such as ion channels [17,19,20,24,[28][29][30][31], there is a recent interest in understanding how ATP controls the lytic action of pore-forming toxins (PFTs) [22,26,27,[32][33][34]. PFTs introduce unregulated conducting pathways into the host cell plasmalemma [35][36][37][38][39], which is expected to yield direct cytolysis.…”

Section: Introductionmentioning

confidence: 99%

Purinergic control of lysenin’s transport and voltage-gating properties

Bryant

Shrestha

Carnig

et al. 2016

Purinergic Signalling

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Lysenin, a pore-forming protein extracted from the coelomic fluid of the earthworm Eisenia foetida, manifests cytolytic activity by inserting large conductance pores in host membranes containing sphingomyelin. In the present study, we found that adenosine phosphates control the biological activity of lysenin channels inserted into planar lipid membranes with respect to their macroscopic conductance and voltage-induced gating. Addition of ATP, ADP, or AMP decreased the macroscopic conductance of lysenin channels in a concentration-dependent manner, with ATP being the most potent inhibitor and AMP the least. ATP removal from the bulk solutions by buffer exchange quickly reinstated the macroscopic conductance and demonstrated reversibility. Singlechannel experiments pointed to an inhibition mechanism that most probably relies on electrostatic binding and partial occlusion of the channel-conducting pathway, rather than ligand gating induced by the highly charged phosphates. The Hill analysis of the changes in macroscopic conduction as a function of the inhibitor concentration suggested cooperative binding as descriptive of the inhibition process. Ionic screening significantly reduced the ATP inhibitory efficacy, in support of the electrostatic binding hypothesis. In addition to conductance modulation, purinergic control over the biological activity of lysenin channels has also been observed to manifest as changes of the voltage-induced gating profile. Our analysis strongly suggests that not only the inhibitor's charge but also its ability to adopt a folded conformation may explain the differences in the observed influence of ATP, ADP, and AMP on lysenin's biological activity.

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ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion

Cited by 81 publications

References 84 publications

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

Hypoglycemia, Chronic Kidney Disease, and Diabetes Mellitus

Purinergic control of lysenin’s transport and voltage-gating properties

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