Electrophysiology of the pancreatic β-cell

Ashcroft, Frances M.; Rorsman, Patrik

doi:10.1016/0079-6107(89)90013-8

Cited by 1,039 publications

(937 citation statements)

References 198 publications

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“…To verify that this was not an effect specific to the excised patch configuration, we studied whole-cell currents. The cells were voltageclamped at −70 mV, on top of which voltage excursions of 5 mV (200 ms) were superimposed at a rate of 0.5 Hz, a protocol reflecting K ATP channel conductance in the beta cell [19,20]. Whole-cell input conductance in the presence of 0.1 mmol/l ATP and 0.1 mmol/l ADP was found to be around 0.4 nS, which slightly decreased with time (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The fact that the beta-cell membrane potential is mainly determined by the activity of the K ATP channel [19] together with reports showing that K ATP channel activity is not regulated normally in diabetic animal models [25], point to an important link between diabetes and a disturbed K ATP channel function. One possible explanation to this is a decreased metabolic activity in the diabetic state, affecting the ability of glucose to increase the ATP/ADP ratio.…”

Section: Discussionmentioning

confidence: 99%

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Long-Chain CoA esters activate human pancreatic beta-cell K ATP channels: potential role in Type 2 diabetes

et al. 2004

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Aims/hypothesis. The ATP-regulated potassium (K ATP ) channel in the pancreatic beta cell couples the metabolic state to electrical activity. The primary regulator of the K ATP channel is generally accepted to be changes in ATP/ADP ratio, where ATP inhibits and ADP activates channel activity. Recently, we showed that long-chain CoA (LC-CoA) esters form a new class of potent K ATP channel activators in rodents, as studied in inside-out patches. Methods. In this study we have investigated the effects of LC-CoA esters in human pancreatic beta cells using the inside-out and whole-cell configurations of the patch clamp technique. Results. Human K ATP channels were potently activated by acyl-CoA esters with a chain length exceeding 12 carbons. Activation by LC-CoA esters did not require the presence of Mg 2+ or adenine nucleotides. A detailed characterization of the concentration-dependent relationship showed an EC 50 of 0.7±0.1 µmol/l. Furthermore, in the presence of an ATP/ADP ratio of 10 (1.1 mmol/l total adenine nucleotides), whole-cell K ATP channel currents increased approximately sixfold following addition of 1 µmol/l LC-CoA ester. The presence of 1 µmol/l LC-CoA in the recording pipette solution increased beta-cell input conductance, from 0.5±0.2 nS to 2.5±1.3 nS. Conclusion/interpretation. Taken together, these results show that LC-CoA esters are potent activators of the K ATP channel in human pancreatic beta cells. The fact that LC-CoA esters also stimulate K ATP channel activity recorded in the whole-cell configuration, points to the ability of these compounds to have an important modulatory role of human beta-cell electrical activity under both physiological and pathophysiological conditions. [Diabetologia (2004) essential function has been included in the model of glucose-induced insulin secretion. In this model, increases in blood glucose levels lead to metabolism of glucose which generates an increase in the ATP/ADP ratio. The consensus view is that increases in the ATP/ADP ratio promote closure of the beta-cell K ATP channel, thereby depolarizing the cell membrane resulting in opening of voltage-dependent Ca 2+ channels. The subsequent rise in cytoplasmic free Ca 2+ concentration triggers a series of events leading to exocytosis of insulin. Hence, the K ATP channel provides a critical link between glucose metabolism, electrical activity and insulin secretion in the pancreatic beta cell.The most important molecular regulators of K ATP channel activity are believed to be adenine nucleo-ATP-sensitive potassium (K ATP ) channels play a key role in the coupling between cellular metabolism and electrical activity in a wide range of tissues. Since the discovery of these channels in the beta cell [1], their

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-Chain CoA esters activate human pancreatic beta-cell K ATP channels: potential role in Type 2 diabetes

et al. 2004

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“…The main pathway of glucose-stimulated insulin secretion is well-established (Ashcroft and Rorsman, 1989;Misler et al, 1992;Henquin, 2000). Glucose enters the β-cell through GLUT glucose transporters and is then metabolized.…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling and statistical analysis of calcium-regulated insulin granule exocytosis in β-cells from mice and humans

Pedersen

Cortese

Eliasson

2011

Progress in Biophysics and Molecular Biology

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“…The most important modulators of K ATP channel gating are adenine nucleotides: in particular, ATP closes the channel by binding to Kir6.2, whereas interaction of Mg-nucleotides (MgATP, MgADP) with the nucleotide-binding domains (NBDs) of SUR1 stimulates channel activity and reverses channel inhibition by ATP [21][22][23]. Nucleotide modulation enables K ATP channels to couple changes in plasma glucose levels to changes in insulin secretion [24,25].…”

Section: Introductionmentioning

confidence: 99%

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

Girard

Shimomura

Proks

et al. 2006

Pflugers Arch - Eur J Physiol

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ATP-sensitive potassium (K ATP ) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.2 inhibits, whereas interaction of Mg-nucleotides with SUR, activates the channel. Heterozygous activating mutations in Kir6.2 (KCNJ11) are a common cause of neonatal diabetes (ND). We assessed the functional effects of six novel Kir6.2 mutations associated with ND: H46Y, N48D, E227K, E229K, E292G, and V252A. K ATP channels were expressed in Xenopus oocytes and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of SUR). All mutations reduced the sensitivity of the K ATP channel to inhibition by MgATP, and enhanced whole-cell K ATP currents. Two mutations (E227K, E229K) also enhanced the intrinsic open probability of the channel, thereby indirectly reducing the channel ATP sensitivity. The other four mutations lie close to the predicted ATP-binding site and thus may affect ATP binding. In pancreatic beta cells, an increase in the K ATP current is expected to reduce insulin secretion and thereby cause diabetes. None of the mutations substantially affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting patients carrying these mutations may respond to these drugs.

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Electrophysiology of the pancreatic β-cell

Cited by 1,039 publications

References 198 publications

Long-Chain CoA esters activate human pancreatic beta-cell K ATP channels: potential role in Type 2 diabetes

Long-Chain CoA esters activate human pancreatic beta-cell K ATP channels: potential role in Type 2 diabetes

Mathematical modeling and statistical analysis of calcium-regulated insulin granule exocytosis in β-cells from mice and humans

Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

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