Lipids modulate ligand binding to sulphonylurea receptors

1 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. 2 Lipids (100–300  μ M ) 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 2.3 OCoA inhibited radioligand binding to SUR completely, with IC 50 values ranging from 6 to 44  μ M . 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. 4 DOGS‐NTA inhibited radioligand binding to SUR by 40–88%, with IC 50 values ranging from 38 to 120  μ M . 5 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. 6 Radioligand binding to SUR2A but not to the other SUR subtypes was slightly (10–20%) stimulated by lipids at concentrations ∼10 × lower than required for inhibition. 7 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  μ M ) are used to interfere with the action of sulphonylureas and openers on K ATP channel activity.British Journal of Pharmacology (2005) 145 , 907–915. doi: 10.1038/sj.bjp.0706252