Document Detail

Lipids modulate ligand binding to sulphonylurea receptors.
MedLine Citation:
PMID:  15895108     Owner:  NLM     Status:  MEDLINE    
ATP-sensitive K(+) channels (K(ATP) channels) are complexes of inwardly rectifying K(+) channels (Kir6.x) and sulphonylurea receptors (SURs). Kir6.2-containing channels are closed by ATP binding to Kir6.2, and opened by MgADP binding to SUR. Channel activity is modulated by synthetic compounds such as the channel-blocking sulphonylureas and the K(ATP) channel openers, which both act by binding to SUR. By interacting with Kir6.2, phosphatidylinositol-4,5-bisphosphate (PIP(2)) and oleoyl-coenzyme A (OCoA) decrease the ATP-sensitivity of the channel and abolish the effect of the synthetic channel modulators. Here, we have investigated whether lipids and related compounds interfered with the binding of the sulphonylurea, glibenclamide (GBC) and of the opener, N-cyano-N'-(1,1-dimethylpropyl)-N''-3-pyridylguanidine (P1075), to the SUR subtypes. Lipids (100-300 microM) inhibited binding of [(3)H]GBC and [(3)H]P1075 to SUR subtypes in the rank order OCoA>dioleylglycerol-succinyl-nitriloacetic acid (DOGS-NTA)>oleate>malonyl-CoA>PIP(2.)OCoA inhibited radioligand binding to SUR completely, with IC(50) values ranging from 6 to 44 microM. Inhibition was reversed by increasing the concentration of the radioligands in agreement with an essentially competitive mechanism. MgATP and coexpression with Kir6.2 decreased the potency of OCoA. DOGS-NTA inhibited radioligand binding to SUR by 40-88%, with IC(50) values ranging from 38 to 120 microM. Poly-lysine increased radioligand binding to SUR by up to 30% but did not affect much the inhibition of ligand binding by OCoA and DOGS-NTA. Radioligand binding to SUR2A but not to the other SUR subtypes was slightly (10-20%) stimulated by lipids at concentrations approximately 10 x lower than required for inhibition. The data show that certain lipids, at high concentrations, interact with SUR and inhibit the binding of GBC and P1075; with SUR2A, a modest stimulation of ligand binding precedes inhibition. Regarding K(ATP) channel activity, these effects will be overruled by the interaction of the lipids with Kir6.2 at lower (physiological) concentrations. They are, however, of pharmacological importance and must be taken into account if high concentrations of these compounds (e.g. OCoA>10 microM) are used to interfere with the action of sulphonylureas and openers on K(ATP) channel activity.
Alexander Klein; Jochen Lichtenberg; Damian Stephan; Ulrich Quast
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  145     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-08-01     Completed Date:  2006-01-17     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  907-15     Citation Subset:  IM    
Department of Pharmacology and Toxicology, Medical Faculty, University of Tübingen, Wilhelmstr. 56, D-72074 Tübingen, Germany.
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MeSH Terms
ATP-Binding Cassette Transporters / drug effects*,  genetics,  metabolism
Acyl Coenzyme A / pharmacology*
Cells, Cultured
Dose-Response Relationship, Drug
Drug Interactions
Glyburide / metabolism
Guanidines / metabolism
Lysine / analogs & derivatives*,  pharmacology
Oleic Acids / pharmacology*
Phosphatidylinositol 4,5-Diphosphate / pharmacology
Polylysine / metabolism
Potassium Channels / drug effects*,  genetics,  metabolism
Potassium Channels, Inwardly Rectifying / drug effects*,  genetics,  metabolism
Pyridines / metabolism
Receptors, Drug / drug effects*,  genetics,  metabolism
Succinates / pharmacology*
Reg. No./Substance:
0/ATP-Binding Cassette Transporters; 0/Acyl Coenzyme A; 0/Guanidines; 0/Kir6.2 channel; 0/N(alpha),N(alpha)-bis(carboxymethyl)-N(epsilon)-(1,2-dioleyl-sn-glycero-3-succinyl)-L-lysine; 0/Oleic Acids; 0/Phosphatidylinositol 4,5-Diphosphate; 0/Potassium Channels; 0/Potassium Channels, Inwardly Rectifying; 0/Pyridines; 0/Receptors, Drug; 0/Succinates; 0/sulfonylurea receptor; 10238-21-8/Glyburide; 1716-06-9/oleoyl-coenzyme A; 25104-18-1/Polylysine; 56-87-1/Lysine; 60559-98-0/N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine

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