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Long‐chain acyl‐CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of Katp channels by the same mechanism

Phosphatidylinositol phosphates (PIPs, e.g. PIP2) and long‐chain acyl‐CoA esters (e.g. oleoyl‐CoA) are potent activators of Katp channels that are thought to link Katp channel activity to the cellular metabolism of PIPs and fatty acids. Here we show that the two types of lipid act by the same mechanism: oleoyl‐CoA potently reduced the ATP sensitivity of cardiac (Kir6.2/SUR2A) and pancreatic (Kir6.2/SUR1) Katp channels in a way very similar to PIP2. Mutations (R54Q, R176A) in the C‐ and N‐terminus of Kir6.2 that greatly reduced the PIP2 modulation of ATP sensitivity likewise reduced the modulation by oleoyl‐CoA, indicating that the two lipids interact with the same site. Polyvalent cations reduced the effect of oleoyl‐CoA and PIP2 on the ATP sensitivity with similar potency suggesting that electrostatic interactions are of similar importance. However, experiments with differently charged inhibitory adenosine phosphates (ATP4‐, ADP3‐ and 2′(3′)‐O‐(2,4,6‐trinitrophenyl)adenosine 5′‐monophosphate (TNP‐AMP2‐)) and diadenosine tetraphosphate (Ap4A5‐) ruled out a mechanism where oleoyl‐CoA or PIP2 attenuate ATP inhibition by reducing ATP binding through electrostatic repulsion. Surprisingly, CoA (the head group of oleoyl‐CoA) did not activate but inhibited Katp channels (IC50= 265 ± 33 μM). We provide evidence that CoA and diadenosine polyphosphates (e.g. Ap4A) are ligands of the inhibitory ATP‐binding site on Kir6.2.