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ATPase activity of the sulfonylurea receptor: a catalytic function for the K_ATP channel complex

MARTIN BIENENGRAEBER^*, ALEXEY E. ALEKSEEV^*, M. ROSELLE ABRAHAM^*, ANTONIO J. CARRASCO^*, CHRISTOPHE MOREAU, MICHEL VIVAUDOU, PETRAS P. DZEJA^* and ANDRE TERZIC^*1

^* Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA; and
CEA, DBMS, Laboratoire de Biophysique Moléculaire et Cellulaire, 38054 Grenoble, France

¹Correspondence: Guggenheim 7, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905, USA. E-mail: terzic.andre{at}mayo.edu

ATP-sensitive K⁺ (K_ATP) channels are unique metabolic sensors formed by association of Kir6.2, an inwardly rectifying K⁺ channel, and the sulfonylurea receptor SUR, an ATP binding cassette protein. We identified an ATPase activity in immunoprecipitates of cardiac K_ATP channels and in purified fusion proteins containing nucleotide binding domains NBD1 and NBD2 of the cardiac SUR2A isoform. NBD2 hydrolyzed ATP with a twofold higher rate compared to NBD1. The ATPase required Mg²⁺ and was insensitive to ouabain, oligomycin, thapsigargin, or levamisole. K1348A and D1469N mutations in NBD2 reduced ATPase activity and produced channels with increased sensitivity to ATP. K_ATP channel openers, which bind to SUR, promoted ATPase activity in purified sarcolemma. At higher concentrations, openers reduced ATPase activity, possibly through stabilization of MgADP at the channel site. K1348A and D1469N mutations attenuated the effect of openers on K_ATP channel activity. Opener-induced channel activation was also inhibited by the creatine kinase/creatine phosphate system that removes ADP from the channel complex. Thus, the K_ATP channel complex functions not only as a K⁺ conductance, but also as an enzyme regulating nucleotide-dependent channel gating through an intrinsic ATPase activity of the SUR subunit. Modulation of the channel ATPase activity and/or scavenging the product of the ATPase reaction provide novel means to regulate cellular functions associated with K_ATP channel opening.—Bienengraeber, M., Alekseev, A. E., Abraham, M. R., Carrasco, A. J., Moreau, C., Vivaudou, M., Dzeja, P. P., Terzic, A. ATPase activity of the sulfonylurea receptor: a catalytic function for the K_ATP channel complex.

Key Words: ATP-sensitive K⁺ channels • enzyme • ABC proteins • nucleotide binding domains • potassium channel openers • Kir6.2 • SUR

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