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Lipids modulate ligand binding to sulphonylurea receptors
Alexander Klein1, Jochen Lichtenberg, Damian Stephan
1Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstr. 56, D-72074 Tübingen, Germany.
British Journal of Pharmacology
|May 17, 2005
Summary
Certain lipids, particularly oleoyl-coenzyme A (OCoA), inhibit the binding of glibenclamide and P1075 to sulphonylurea receptors (SURs) at high concentrations. These lipid-SUR interactions are pharmacologically significant for K(ATP) channel modulation.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- ATP-sensitive K(+) channels (K(ATP) channels) are crucial for cellular energy homeostasis, composed of Kir6.x and SUR subunits.
- K(ATP) channel activity is regulated by intracellular ATP levels and modulated by synthetic drugs like sulphonylureas and openers, which bind to SURs.
- Lipids such as phosphatidylinositol-4,5-bisphosphate (PIP(2)) and oleoyl-coenzyme A (OCoA) interact with Kir6.2, reducing ATP sensitivity and abolishing drug effects.
Purpose of the Study:
- To investigate how lipids and related compounds interfere with the binding of glibenclamide (GBC) and P1075 to SUR subtypes.
- To determine the rank order of lipid inhibition on radioligand binding to SURs.
- To elucidate the mechanism and potential pharmacological relevance of lipid-SUR interactions.
Main Methods:
- Radioligand binding assays using [(3)H]GBC and [(3)H]P1075 to assess binding to SUR subtypes.
- Testing the inhibitory effects of various lipids (OCoA, DOGS-NTA, oleate, malonyl-CoA, PIP(2)) on radioligand binding.
- Investigating the influence of MgATP, coexpression with Kir6.2, and poly-lysine on lipid inhibition.
Main Results:
- Lipids inhibited radioligand binding to SUR subtypes, with OCoA showing the strongest inhibition (IC(50) 6-44 microM).
- Inhibition by OCoA was competitive and dose-dependent, while DOGS-NTA showed moderate inhibition (IC(50) 38-120 microM).
- Lipids showed a modest stimulatory effect on SUR2A binding at lower concentrations before inhibition at higher concentrations.
Conclusions:
- Specific lipids, at high concentrations, directly interact with SURs and inhibit the binding of GBC and P1075.
- These lipid-SUR interactions have pharmacological implications, particularly when high lipid concentrations are present.
- While lipid interactions with Kir6.2 dominate at physiological concentrations, SUR interactions are important for understanding drug efficacy at higher concentrations.