Inwardly rectifying Kir2.1 currents in human β-cells control electrical activity: characterisation and mathematical modelling.
Pancreatic β-cells fire action potentials as do cardiac cells and neurons, and electrical activity plays a central role in glucose-stimulated insulin secretion, which is disturbed in diabetes. The inwardly rectifying Kir2.1 potassium channels (KCNJ2 gene) control cardiac electrical activity by stabilising the interspike interval. Loss-of-function abnormalities in cardiac Kir2.1 currents can lead to the long QT syndrome and alterations of cardiac excitability, and patients with some forms of long QT syndrome suffer from over-secretion of insulin, hyperinsulinemia and symptomatic hypoglycemia. The KCNJ2 gene is also expressed in human pancreatic islets, and we show that functional Kir2.1 currents are present in human β-cells. We characterised the human Kir2.1 β-cell current, and included it in a recent mathematical model of electrical activity in human β-cells. Based on our simulations we propose that Kir2.1 currents control the interspike interval, and predict that blocking Kir2.1 channels increases the action potential frequency, which should augment the rate of insulin secretion. Vice versa, the model suggests that hyperactive Kir2.1 channels may lead to reduced insulin secretion. Our findings provide a putative link between increased insulin secretion and the long QT syndrome, and give novel insight into normal and disturbed β-cell function.
Department of Information Engineering, University of Padua, Via Gradenigo 6/B, 35131 Padua, Italy. Electronic address: michela.riz@dei.unipd.it.
Michela
M
Riz
Alberta Diabetes Institute, Department of Pharmacology, University of Alberta, 5-126A Li Ka Shing Center for Health Research Innovation, Edmonton, Alberta T6G 2E1, Canada. Electronic address: mbraun1@ualberta.ca.
Matthias
M
Braun
Alberta Diabetes Institute, Department of Pharmacology, University of Alberta, 5-126A Li Ka Shing Center for Health Research Innovation, Edmonton, Alberta T6G 2E1, Canada. Electronic address: xichen@ualberta.ca.
Xichen
X
Wu
Department of Information Engineering, University of Padua, Via Gradenigo 6/B, 35131 Padua, Italy. Electronic address: pedersen@dei.unipd.it.
Morten Gram
MG
Pedersen
D000200:Action Potentials; D055724:Electrophysiological Phenomena; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008133:Long QT Syndrome / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; C489457:KCNJ2 protein, human; D024661:Potassium Channels, Inwardly Rectifying
Action potential firing; Electrical activity; Insulin secretion; Ion channels; Mathematical model; Pancreatic beta-cells