The Common Single Nucleotide Polymorphism E23K in KIR6.2 Sensitizes Pancreatic β-Cell ATP-Sensitive Potassium Channels Toward Activation Through Nucleoside Diphosphates
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.
Address correspondence and reprint requests to Dr. Christina Schwanstecher, Institut für Pharmakologie und Toxikologie, Universität Braunschweig, Mendelssohnstraβe 1, 38106 Braunschweig, Germany. E-mail:.
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.