ATPase of the sulfonylurea receptor and K_ATP channel gating

Sulfonylurea receptors (SUR) associate with Kir6.2 proteins to form ATP-sensitive K+ (K_ATP) channels with cardioprotective properties. We recently discovered an ATPase activity in the nucleotide-binding domain NBD2 of SUR, but its role in regulating K_ATP channels remains undefined. Here we show, that phosphate analogs orthovanadate (V_i) and beryllium fluoride (BeF_x) inhibit ATPase activity by stabilizing MgADP at NBD2. While FeF_x inhibited, V_i promoted opening of K_ATP channels, suggesting the existence of two different transitional conformational states in the ATPase cycle associated with negative (SUR·MgADP·BeF_x) or positive (SUR*·MgADP·V_i) KATP channel gating. Potassium channel openers (KCO), which activate K_ATP 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 K_ATP channels. KCO-induced K_ATP channel opening was abolished by BeF_x and facilitated by V_i, 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 K_ATP channels by cardio-protective drugs.