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Long‐chain acyl‐CoA esters and phosphatidylinositol phosphates modulate ATP inhibition of K atp channels by the same mechanism
Author(s) -
Schulze Dirk,
Rapedius Markus,
Krauter Tobias,
Baukrowitz Thomas
Publication year - 2003
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.2003.00357.x
Subject(s) - phosphatidylinositol , chemistry , acyl coa , adenosine triphosphate , biochemistry , mechanism (biology) , kir6.2 , biophysics , microbiology and biotechnology , enzyme , biology , phosphorylation , philosophy , epistemology , protein subunit , gene
Phosphatidylinositol phosphates (PIPs, e.g. PIP 2 ) and long‐chain acyl‐CoA esters (e.g. oleoyl‐CoA) are potent activators of K atp channels that are thought to link K atp 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) K atp channels in a way very similar to PIP 2 . Mutations (R54Q, R176A) in the C‐ and N‐terminus of Kir6.2 that greatly reduced the PIP 2 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 PIP 2 on the ATP sensitivity with similar potency suggesting that electrostatic interactions are of similar importance. However, experiments with differently charged inhibitory adenosine phosphates (ATP 4‐ , ADP 3‐ and 2′(3′)‐ O ‐(2,4,6‐trinitrophenyl)adenosine 5′‐monophosphate (TNP‐AMP 2‐ )) and diadenosine tetraphosphate (Ap 4 A 5‐ ) ruled out a mechanism where oleoyl‐CoA or PIP 2 attenuate ATP inhibition by reducing ATP binding through electrostatic repulsion. Surprisingly, CoA (the head group of oleoyl‐CoA) did not activate but inhibited K atp channels (IC 50 = 265 ± 33 μM). We provide evidence that CoA and diadenosine polyphosphates (e.g. Ap 4 A) are ligands of the inhibitory ATP‐binding site on Kir6.2.