Sulfonylurea receptors (SUR) associate with Kir6.2 proteins to form ATP-sensitive K+ (KATP) channels with cardioprotective properties. We recently discovered an ATPase activity in the nucleotide-binding domain NBD2 of SUR, but its role in regulating KATP channels remains undefined. Here we show, that phosphate analogs orthovanadate (Vi) and beryllium fluoride (BeFx) inhibit ATPase activity by stabilizing MgADP at NBD2. While FeFx inhibited, Vi promoted opening of KATP channels, suggesting the existence of two different transitional conformational states in the ATPase cycle associated with negative (SUR·MgADP·BeFx) or positive (SUR*·MgADP·Vi) KATP channel gating. Potassium channel openers (KCO), which activate KATP channels through SUR, inhibited ATPase activity in cardiac membranes. Mutations in NBD2 that decreased channel ATPase activity have been shown to attenuate opener activation of KATP channels. KCO-induced KATP channel opening was abolished by BeFx and facilitated by Vi, suggesting that openers act via stabilization of the ADP-bound conformational state of SUR. Thus, control of the SUR catalytic activity provides a molecular mechanism underlying regulation of KATP channels by cardio-protective drugs.
|Original language||English (US)|
|Journal||Clinical pharmacology and therapeutics|
|State||Published - Dec 1 2001|
ASJC Scopus subject areas
- Pharmacology (medical)