The common single nucleotide polymorphism E23K in K(IR)6.2 sensitizes pancreatic beta-cell ATP-sensitive potassium channels toward activation through nucleoside diphosphates.
E23K, a common polymorphism in the pore-forming subunit K(IR)6.2 of pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) 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 K(ATP) overactivity and discrete inhibition of insulin release.
Schwanstecher
Christina
C
Institute of Pharmacology and Toxicology, University of Braunschweig, Braunschweig, Germany. c.schwanstecher@tu-bs.de
Neugebauer
Bettina
B
Schulz
Miriam
M
Schwanstecher
Mathias
M
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D006153:Guanosine Diphosphate / Q000494:pharmacology; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*
D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D006153:Guanosine Diphosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate