Glucose-induced Oscillations in Cytoplasmic Free Ca2+Concentration Precede Oscillations in Mitochondrial Membrane Potential in the Pancreatic β-Cell

Kindmark, Henrik; Köhler, Martin; Brown, G. R.; Bränström, Robert; Larsson, Olof; Berggren, Per Olof

doi:10.1074/jbc.m102492200

Cited by 72 publications

(77 citation statements)

References 38 publications

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“…Second, K ATP channels have been considered to play a key role in the oscillatory activity of beta cells [24,32,33,34]. For example, it has been reported recently that a rise in [Ca 2+ ] c lowers ATP production evoking an increase in the K ATP currents which act as a negative feedback to reduce Ca 2+ influx by hyperpolarizing the beta cell [35].…”

Section: Discussionmentioning

confidence: 99%

Oscillations of membrane potential and cytosolic Ca2+ concentration in SUR1−/− beta cells

et al. 2004

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Aims/hypothesis. SUR1(ABCC8) −/− mice lacking functional K ATP channels are an appropriate model to test the significance of K ATP channels in beta-cell function. We examined how this gene deletion interferes with stimulus-secretion coupling. We tested the influence of metabolic inhibition and galanin, whose mode of action is controversial. Methods. Plasma membrane potential (Vm) and currents were measured with microelectrodes or the patch-clamp technique; cytosolic Ca 2+ concentrations ([Ca 2+ ] c ) and mitochondrial membrane potential (∆Ψ) were measured using fluorescent dyes. Results. In contrast to the controls, SUR1 −/− beta cells showed electrical activity even at a low glucose concentration. Continuous spike activity was measured with the patch-clamp technique, but with microelectrodes slow oscillations in Vm consisting of bursts of Ca 2+ -dependent action potentials were detected.

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Section: Discussionmentioning

confidence: 99%

Oscillations of membrane potential and cytosolic Ca2+ concentration in SUR1−/− beta cells

et al. 2004

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“…This has previously been inferred for glucose from parallel measurements of [Ca 2ϩ ] i and rhodamine 123 fluorescence (29) and was demonstrated recently with simultaneous measurements (46), but it not shown previously for DHA and GA. However, in contrast to glucose, neither DHA nor GA produced a detectable increase in NAD(P)H. A possible explanation in the case of GA comes from the suggestion that GA may be oxidized directly by glyceraldehyde-3-phosphate dehydrogenase to produce cytosolic NADH, which is reoxidized via the glycerol phosphate shuttle, feeding into the electron transport chain downstream from mitochondrial NADH (22).…”

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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“…Mitochondrial Ca 2ϩ uptake has long been known to stimulate the turnover of matrix dehydrogenases coupled to the tricarboxylic acid cycle. This activity provides substrates for mitochondrial respiration, which can promote an increase in ⌬⌿ m (26,37,39,40).…”

Section: Discussionmentioning

confidence: 99%

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

Hail

Konopleva

Sporn

et al. 2004

Journal of Biological Chemistry

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The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel anticancer agent that induces apoptosis in tumor cells. The cytotoxic stress underpinning CDDO-induced apoptosis has not been established. This study compared and contrasted the effects of CDDO on COLO 16 human skin cancer cells and their respiration-deficient ( 0 ) clones to elucidate the stress signal responsible for initiating apoptosis. CDDO promoted apoptosis in COLO 16 cells in a doseand time-dependent manner. The 0 clones appeared to be more sensitive to CDDO-induced apoptosis implying that the disruption of mitochondrial respiration was not directly associated with triggering cell death. After a 4-h exposure to CDDO, mitochondrial inner transmembrane potential-sensitive dyes revealed mitochondrial hyperpolarization in the COLO 16 cells and mitochondrial depolarization in the 0 clones. Electron microscopy illustrated that this exposure also promoted mitochondrial condensation, endoplasmic reticulum dilation, and chromatin condensation in the COLO 16 cells. Endoplasmic reticulum dilation and chromatin condensation were also observed in the 0 clones, but the mitochondria in these cells were markedly swollen implying that the disruption of intracellular Ca 2؉ homeostasis was associated with cell death. A Ca 2؉ -sensitive dye confirmed that CDDO increased cytoplasmic free Ca Triterpenoids derived from plants are used for medicinal purposes in many Asian countries and have been reported to have anticancer activity (1). Many of the plant-derived triterpenoids are considered weak anti-inflammatory and/or anticancer agents, which has encouraged the identification of novel synthetic analogues with greater potency (2). One such analogue, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), 1 has gained recognition as a promising cancer chemopreventive and therapeutic agent (3). In vitro studies have shown that nanomolar concentrations of CDDO can inhibit the proliferation of various human tumor cell types (3, 4), suppress the activity of inflammatory cytokines such as interferon-␥, interleukin-1, and tumor necrosis factor (2, 3), and inhibit the induction of inflammatory mediators such as cyclooxygenase-2 and nitric oxide synthase (2, 3). More recently, low micromolar concentrations (Յ10 M) of CDDO have been shown to induce apoptosis in human myeloid (5, 6) and lymphocytic leukemia cells (7), osteosarcoma cells (8), and breast cancer cells (4).Apoptosis is the mechanism utilized by metazoans to eliminate redundant or potentially deleterious cells and is considered an essential process for regulating tissue homeostasis. Apoptosis induction is arguably the most potent defense against cancer making it a desirable end point for both chemoprevention (9) and chemotherapy (10). Apoptosis is a relatively linear process. It is triggered by an initiation phase that is highly varied depending on cell type and the underlying stress stimulus (e.g. oxidative stress, DNA damage, ion fluctuations, and cytokines). This is followed by an effe...

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Glucose-induced Oscillations in Cytoplasmic Free Ca2+Concentration Precede Oscillations in Mitochondrial Membrane Potential in the Pancreatic β-Cell

Cited by 72 publications

References 38 publications

Oscillations of membrane potential and cytosolic Ca2+ concentration in SUR1−/− beta cells

Oscillations of membrane potential and cytosolic Ca2+ concentration in SUR1−/− beta cells

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

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

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