KATP-channels in beta-cells in tissue slices are directly modulated by millimolar ATP

In pancreatic beta-cells, inhibition of K_ATP-channels plays a pivotal role in signal transduction of glucose-induced insulin release. However, the extreme sensitivity of K_ATP-channels to its ligand ATP as found in inside-out patches is not directly compatible with modulation of these channels at physiological [ATP]_i. We studied K_ATP-channel sensitivity to ATP in beta-cells in dispersed culture and in fresh pancreatic tissue slices. Physiological [ATP]_i blocks more than 99% of K_ATP-channels in cultured beta-cells, while only 90% in beta-cells in slices, indicating reduced sensitivity to ATP in the fresh slices. Applying cytosolic factors like ADP, phosphatidylinositol-4,5-bisphosphate (PIP₂) or oleoyl-CoA did not restore the K_ATP-channel sensitivity in cultured beta-cells. Our data suggest that interaction between SUR1 and Kir6.2 subunit of the K_ATP-channel could be a factor in sensitivity modulation. Tissue slices are the first beta-cell preparation to study direct K_ATP-channel modulation by physiological [ATP]_i.