The Common Single Nucleotide Polymorphism E23K in KIR6.2 Sensitizes Pancreatic β-Cell ATP-Sensitive Potassium Channels Toward Activation Through Nucleoside Diphosphates
- From the Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany
Abstract
E23K, a common polymorphism in the pore-forming subunit KIR6.2 of pancreatic β-cell ATP-sensitive K+ (KATP) channels, is functionally relevant and thus might play a major role in the pathophysiology of common type 2 diabetes. In this study, we show that in the simultaneous presence of activatory and inhibitory nucleotides, the polymorphism exerts opposite effects on the potencies of these modulators: channel opening through nucleoside diphosphates is facilitated, whereas sensitivity toward inhibition through ATP is slightly decreased. The results support the conclusion that E23K predisposes to type 2 diabetes by changing the channel’s response to physiological variation of cytosolic nucleotides, resulting in KATP overactivity and discrete inhibition of insulin release.
Footnotes
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Address correspondence and reprint requests to Dr. Christina Schwanstecher, Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany. E-mail: c.schwanstecher{at}tu-bs.de.
Received for publication 19 March 2002 and accepted in revised form 23 April 2002.
DMEM, Dulbecco’s modified Eagle’s medium; EC50, half-maximal effective concentration; Emax, maximal effect; GDP, guanosine 5′-diphosphate; HG, high glucose; IC50, half-maximal inhibitory concentration value; KATP channel, ATP-sensitive K+ channel; Kir channel, inwardly rectifying potassium channel; NDPK, nucleoside diphosphate kinase; PO, open probability; SNP, single nucleotide polymorphism; SUR, sulfonylurea receptor.
The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.
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