Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells

Bokvist, Krister; Olsen, Henrik Baare; Høy, Marianne; Gotfredsen, Carsten F.; Holmes, William F.; Buschard, Karsten; Rorsman, Patrik; Gromada, Jesper

doi:10.1007/s004249900076

Cited by 92 publications

(107 citation statements)

References 33 publications

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“…At low intracellular ATP levels (0.3 mmol/l), the whole-cell conductance averaged 276 ± 94 pS (n = 3), which was reduced to 140 ± 21 pS (n = 3) when ATP was included at a high (5 mmol/l) concentration in the pipette solution. It is worth pointing out that the magnitude of the whole-cell K ATP conductance in the ␣-cell is small compared with that observed in mouse ␤-cells (10 nS) (20) and rat ␣-cells (20 nS) (11). The single-channel conductance (␥) of the K ATP channel has been reported to be 19 pS with the intracellular solutions used in these experiments (22).…”

Section: E F B a Cmentioning

confidence: 74%

“…The finding that glucagon secretion is Ca 2+ -dependent, coupled with the fact that glucagon release is suppressed by glucose, suggests that the ␣-cells must be electrically silent at elevated glucose concentrations, contrary to the situation in the ␤-cell. Thus, it is surprising that ATP-sensitive potassium channels (i.e., channels that are inhibited by an increase in the intracellular ATP concentration [K ATP channels]) have recently been documented in rat ␣-cells (11). So far, no data about the electrophysiology of mouse ␣-cells are available.…”

Section: Tight Coupling Between Electrical Activity and Exocytosis Inmentioning

confidence: 99%

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Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.

et al. 2000

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␣-Cells were identified in preparations of dispersed mouse islets by immunofluorescence microscopy. A high fraction of ␣-cells correlated with a small cell size measured as the average cell diameter (10 µm) and whole-cell capacitance (<4 pF). The ␣-cells generated action potentials at a low frequency (1 Hz) in the absence of glucose. These action potentials were reversibly inhibited by elevation of the glucose concentration to 20 mmol/l. The action potentials originated from a membrane potential more negative than -50 mV, had a maximal upstroke velocity of 5 V/s, and peaked at +1 mV. Voltage-clamp experiments revealed the ionic conductances underlying the generation of action potentials. ␣-Cells are equipped with a delayed tetraethyl-ammonium-blockable outward current (activating at voltages above -20 mV), a large tetrodotoxin-sensitive Na + current (above -30 mV; peak current 200 pA at +10 mV), and a small Ca 2+ current (above -50 mV; peak current 30 pA at +10 mV). The latter flowed through -conotoxin GVIA (25%)-and nifedipine-sensitive (50%) Ca G lucagon is a major catabolic and hyperglycemic hormone of 29 amino acids and is secreted from the ␣-cells of the islets of Langerhans (1). Its main biological effect is the regulation of glucose metabolism by enhancing synthesis and mobilization of glucose in the liver. Normally, secretion of the hormone is stimulated by low blood glucose (2), amino acids (3), and a variety of hormones and neurotransmitters, such as adrenaline, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide-1 (4,5). Hyperglycemia and fatty acids are the main inhibitors (6), but the islet hormones insulin and somatostatin (4) also appear to reduce glucagon secretion, possibly by a paracrine mechanism (7). Whereas insulin levels are inadequately low in hyperglycemic diabetic subjects, glucagon levels are actually elevated, and this increase exacerbates the disease (8). The reason for this abnormality is unknown, and studies on ␣-cells are complicated by the scarcity of islet tissue and the low occurrence of ␣-cells compared with ␤-cells. Therefore, how glucose physiologically regulates secretion in the ␣-cell remains unknown. Electrical activity in glucagon-secreting cells has been observed using several experimental approaches (5,9,10), and it is, at least in part, attributable to voltage-gated Ca 2+ channels. Available evidence also suggests that glucagon release is a Ca 2+ -dependent process. Indeed, capacitance measurements on single rat ␣-cells revealed a close relationship between N-type Ca 2+ channels and the secretory granules under basal conditions, whereas L-type Ca 2+ channels appeared more important when secretion was stimulated with adrenaline (5). The finding that glucagon secretion is Ca 2+ -dependent, coupled with the fact that glucagon release is suppressed by glucose, suggests that the ␣-cells must be electrically silent at elevated glucose concentrations, contrary to the situation in the ␤-cell. Thus, it is surprising that ATP-sensitive potassium channels (i.e...

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Section: E F B a Cmentioning

confidence: 74%

Section: Tight Coupling Between Electrical Activity and Exocytosis Inmentioning

confidence: 99%

Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.

et al. 2000

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“…In situ hybridization has demonstrated the expression of the mRNA-encoding K ATP channel subunits SUR1 and Kir6.2 in rat A cells (31). Moreover, using immunohistochemistry methods, SUR1 and Kir6.2 were localized in A, B, D, and PP cells (32).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, using immunohistochemistry methods, SUR1 and Kir6.2 were localized in A, B, D, and PP cells (32). The sulfonylurea tolbutamide produced a concentration-dependent decrease in the whole-cell K ATP conductance in isolated rat A cells and initiated action-potential firing at 20 mmol/l glucose (31). In addition, capacitance measurements in single A cells indicated that tolbutamide stimulates exocytosis evoked by depolarization or intracellular calcium infusion in these cells (33).…”

Section: Discussionmentioning

confidence: 99%

Gliclazide Directly Inhibits Arginine-Induced Glucagon Release

et al. 2002

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Arginine-stimulated insulin and somatostatin release is enhanced by the sulfonylurea gliclazide. In contrast, gliclazide inhibits the glucagon response. The aim of the present study was to investigate whether this inhibition of glucagon release was mediated by a direct suppressive effect of gliclazide or was secondary to the paracrine effect of released somatostatin. To eliminate the paracrine effects of somatostatin, we first perfused isolated rat pancreata with a medium supplemented with 23% of the standard calcium content. Second, we perifused isolated rat islets with a novel and highly specific antagonist of type 2 somatostatin receptor, DC-41-33 (2 mol/l), which fully antagonizes the suppressive somatostatin effect on rat A cells. Gliclazide (30 mol/l) inhibited glucagon release by 54% in the perfusion experiments, whereas the somatostatin response was nearly abolished. In islet perifusions with DC-41-33, arginineinduced glucagon release was inhibited by 66%. We therefore concluded that gliclazide inhibits glucagon release by a direct action on the pancreatic A cell. Diabetes 51 (Suppl. 3):S381-S384, 2002

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“…Like the beta cell, glucagon-secreting alpha cells are equipped with K ATP -channels [8]. Experiments in which increasing concentrations of tolbutamide and diazoxide (a blocker and an activator of the K ATP -channel, respectively) were used to titrate K ATP -channelsactivity in alpha cells in intact mouse, rat and human islets indicate that glucagon secretion only occurs within a narrow window of K ATPchannel activity [9].…”

Section: Introductionmentioning

confidence: 99%

The glucagon-producing alpha cell: an electrophysiologically exceptional cell

Braun

Rorsman

2010

Diabetologia

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Activation of potassium channels normally serves to reduce cellular activity but recent data indicate that the glucagon-secreting alpha cells are different in this respect and that inhibition of voltage-gated potassium channels results in a paradoxical inhibition of glucagon secretion. Here we discuss these findings and attempt to provide a model for the regulation of glucagon secretion that incorporates these observations.

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Characterisation of sulphonylurea and ATP-regulated K+ channels in rat pancreatic A-cells

Cited by 92 publications

References 33 publications

Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.

Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting alpha-cells.

Gliclazide Directly Inhibits Arginine-Induced Glucagon Release

The glucagon-producing alpha cell: an electrophysiologically exceptional cell

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