Modulation of gating of a metabolically regulated, ATP-dependent K+ channel by intracellular pH in B cells of the pancreatic islet

Misler, Stanley; Gillis, Kevin D.; Tabcharani, Joseph A.

doi:10.1007/bf01870852

Cited by 62 publications

(33 citation statements)

References 18 publications

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“…In fact, studies of excised patches of cardiomyocyte (52) or ␤-cell (53) membranes have shown that micromolar concentrations of amiloride and derivatives can directly inhibit K ATP channels by interacting with the pore. Our results do not rule out the possibility that changes in pH c can influence K ATP channels in ␤-cells (54,55), but preclude the use of amiloride derivatives to test the role of Na ϩ /H ϩ exchange itself and of pH c changes in insulin secretion. We therefore used two other approaches: the NHE1 mutant islets and the direct comparison of insulin secretion and pH c changes in HCO 3 Ϫ and HEPES media.…”

Section: Nhe1 and Islet Cell Ph C Regulation-nacontrasting

confidence: 58%

Glucose-induced Cytosolic pH Changes in β-Cells and Insulin Secretion Are Not Causally Related

Stiernet¹,

Nenquin²,

Moulin³

et al. 2007

Journal of Biological Chemistry

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The contribution of Na ؉ /H ؉ exchange (achieved by NHE proteins) to the regulation of ␤-cell cytosolic pH c , and the role of pH c changes in glucose-induced insulin secretion are disputed and were examined here. Using real-time PCR, we identified plasmalemmal NHE1 and intracellular NHE7 as the two most abundant NHE isoforms in mouse islets. We, therefore, compared insulin secretion, cytosolic free Ca

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Section: Nhe1 and Islet Cell Ph C Regulation-nacontrasting

confidence: 58%

Glucose-induced Cytosolic pH Changes in β-Cells and Insulin Secretion Are Not Causally Related

Stiernet¹,

Nenquin²,

Moulin³

et al. 2007

Journal of Biological Chemistry

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“…This may be due to the GA-induced drop in pH i , which may have effects such as closure of K ATP channels (48,51,52), inhibition of gap junctional conductance (53) (which may be important for electrical coupling to promote oscillatory behavior), and inhibition of PFK-M, the putative generator of the oscillations, because the enzyme has been shown to be extremely pH-sensitive (53,54). Indeed, we previously showed in the glycolyzing muscle extract system that differences in the initial pH of 0.1 unit or less could greatly affect the time of initiation and the period of the oscillations (55).…”

Section: Dihydroxyacetone and Ca 2ϩ Oscillations 40714mentioning

confidence: 99%

Dihydroxyacetone-induced Oscillations in Cytoplasmic Free Ca2+ and the ATP/ADP Ratio in Pancreatic β-Cells at Substimulatory Glucose

Juntti‐Berggren

Webb

Arkhammar

et al. 2003

Journal of Biological Chemistry

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Glucose stimulation of pancreatic ␤-cells causes oscillatory influx of Ca 2؉ , leading to pulsatile insulin secretion. We have proposed that this is due to oscillations of glycolysis and the ATP/ADP ratio, which modulate the activity of ATP-sensitive K ؉ channels. We show here that dihydroxyacetone, a secretagogue that feeds into glycolysis below the putative oscillator phosphofructokinase, could cause a single initial peak in ] i oscillations with a period of minutes, which correspond to oscillations in insulin secretion (1-3). Similar oscillations in insulin secretion are observed in vivo and are abnormal or diminished in type 2 diabetes (4 -6); loss of oscillations may reduce the effectiveness of insulin (7,8) and thus contribute to the development of the disease. In addition to this K ATP channel-mediated action to raise [Ca 2ϩ ] i , there is also a K ATP channel-independent stimulation of secretion by glucose (9, 10), which may involve the ATP/ADP ratio (9) or lipid signals (11). Because oscillations in insulin secretion can be seen under conditions in which [Ca 2ϩ ] i is not changing, it has been proposed that the underlying oscillator is metabolic rather than ionic (12). In particular, we have proposed that the basis of these oscillations in the pancreatic ␤-cell is the spontaneous oscillations of glycolysis and the ATP/ADP ratio due to pulsed action of the muscle isoform of phosphofructokinase (PFK-M), which is present in ␤-cells (13). As demonstrated previously in muscle extracts, such oscillatory behavior can result from autocatalytic activation of PFK-M by its product, fructose 1,6-bisphosphate (Fru-1,6-P 2 ) (14, 15). The occurrence of glycolytic oscillations in the ␤-cell is supported by observations of similar oscillations in [Ca 2ϩ ] i , glucose 6-phosphate, and the ATP/ADP ratio (16,17), as well as oscillatory release of lactate from perifused islets (18).As a further test of this hypothesized role of glycolytic oscillations, we examined the actions of the trioses dihydroxyacetone (DHA) and glyceraldehyde (GA) that on phosphorylation feed into glycolysis downstream of the phosphofructokinase reaction. The trioses can also serve as secretagogues (19 -21), though they have not been shown to cause oscillations in [Ca 2ϩ ] i or insulin secretion. Of the two, GA is the more potent and the more widely studied. However, there is concern that it may not be a suitable glucose mimic in that it causes strong cellular acidification, most likely because of direct metabolism by glyceraldehyde-3-phosphate dehydrogenase and perhaps phosphoglycerate kinase to produce glyceric acid (22). We therefore focused on DHA, although some experiments were also performed with GA for comparison. Furthermore, we previously showed in the glycolyzing muscle extract system that the addition of DHA-P could trigger a pulse of PFK activity by

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“…It should be remembered, however, glucose-stimulated insulin secretion [8][9][10][11]. The inhibition of K ATP channels is a possible mechanism of the intracellular acidic pH effect on insulin secretion [12]; K ATP channels have histidine residues involved in either the inhibition or the activation of the activity in response to a change in the intracellular pH [13,14]. The beneficial role of acidic pH on insulin secretion is supposed to be mainly based on the action of the Na + / H + exchange blocker: inhibitors of Na + /H + exchange caused the enhancement of glucose-stimulated insulin secretion in association with a decrease in the intracellular pH.…”

Section: Proton-sensing Ion Channelsmentioning

confidence: 99%

“…In order to evaluate the role of ability to inhibit K ATP channels and, thereby, to induce depolarization of the cells [12,14]. OGR1 deficiency inhibited insulin secretion at neutral pH 7.4, suggesting that OGR1 is functioning at a physiological pH.…”

Section: In Vivo Analysismentioning

confidence: 99%

Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions

2014

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Abstract. Insulin secretion with respect to pH environments has been investigated for a long time but its mechanism remains largely unknown. Extracellular pH is usually maintained at around 7.4 and, its change has been thought to occur in non-physiological situations. Acidification takes place under ischemic and inflammatory microenvironments, where stimulation of anaerobic glycolysis results in the production of lactic acid. In addition to ionotropic ion channels, such as transient receptor potential V1 (TRPV1) and acid-sensing ion channels (ASICs), metabotropic proton-sensing G proteincoupled receptors (GPCRs) have also been identified recently as proton-sensing machineries. While ionotropic ion channels usually sense strong acidic pH, proton-sensing GPCRs sense pH of 7.6 to 6.0 and have been shown to mediate a variety of biological actions in neutral and mildly acidic pH environments. Studies with receptor knockout mice have revealed that proton-sensing receptors, including ovarian cancer G protein-coupled receptor 1 (OGR1), a proton-sensing GPCRs, play a role in the regulation of insulin secretion and glucose metabolism under physiological conditions. Small molecule 3,5-disubstituted isoxazoles have recently been identified as OGR1 agonists working at neutral pH and have been shown to stimulate pancreatic β-cell differentiation and insulin synthesis. Thus, proton-sensing OGR1 may be an important player for insulin secretion and a potential target for improving β-cell function.

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Modulation of gating of a metabolically regulated, ATP-dependent K+ channel by intracellular pH in B cells of the pancreatic islet

Cited by 62 publications

References 18 publications

Glucose-induced Cytosolic pH Changes in β-Cells and Insulin Secretion Are Not Causally Related

Glucose-induced Cytosolic pH Changes in β-Cells and Insulin Secretion Are Not Causally Related

Dihydroxyacetone-induced Oscillations in Cytoplasmic Free Ca2+ and the ATP/ADP Ratio in Pancreatic β-Cells at Substimulatory Glucose

Role of extracellular proton-sensing OGR1 in regulation of insulin secretion and pancreatic β-cell functions

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