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ATP Sensitivity of the ATP-Sensitive K⁺ Channel in Intact and Permeabilized Pancreatic ß-Cells

From the University Laboratory of Physiology, Oxford University, Oxford, U.K

Address correspondence and reprint requests to Prof. F.M. Ashcroft, University Laboratory of Physiology, Parks Road, Oxford, OX1 3PT, U.K. E-mail: frances.ashcroft{at}physiol.ox.ac.uk

Abbreviations: [ATP]_i, intracellular concentration of ATP; [ATP]_sm, submembrane ATP concentration; K_ATP channel, ATP-sensitive K⁺ channel; LC-CoA, long-chain acyl-CoA; NBD, nucleotide-binding domain; PIP₂, phosphatidylinositol 4,5-bisphosphate; SUR, sulfonylurea receptor

ATP-sensitive K⁺ channels (K_ATP channels) couple cell metabolism to electrical activity and thereby to physiological processes such as hormone secretion, muscle contraction, and neuronal activity. However, the mechanism by which metabolism regulates K_ATP channel activity, and the channel sensitivity to inhibition by ATP in its native environment, remain controversial. Here, we used -toxin to permeabilize single pancreatic ß-cells and measure K_ATP channel ATP sensitivity. We show that the channel ATP sensitivity is approximately sevenfold lower in the permeabilized cell than in the inside-out patch and that this is caused by interaction of Mg-nucleotides with the nucleotide-binding domains of the SUR1 subunit of the channel. The ATP sensitivity observed in permeabilized cells accounts quantitatively for K_ATP channel activity in intact cells. Thus, our results show that the principal metabolic regulators of K_ATP channel activity are MgATP and MgADP.

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