ATPase activity of the sulfonylurea receptor: a catalytic function for the KATP channel complex. FASEB J 2000 Oct;14(13):1943-52
Date
10/12/2000Pubmed ID
11023978DOI
10.1096/fj.00-0027comScopus ID
2-s2.0-0033816117 (requires institutional sign-in at Scopus site) 126 CitationsAbstract
ATP-sensitive K+ (KATP) 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 KATP 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. KATP 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 KATP 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 KATP 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 KATP channel opening.
Author List
Bienengraeber M, Alekseev AE, Abraham MR, Carrasco AJ, Moreau C, Vivaudou M, Dzeja PP, Terzic AMESH terms used to index this publication - Major topics in bold
ATP-Binding Cassette TransportersAdenosine Diphosphate
Adenosine Triphosphatases
Adenosine Triphosphate
Animals
Binding Sites
Creatine Kinase
Electric Conductivity
Guinea Pigs
Ion Channel Gating
Myocardium
Nucleotides
Potassium Channels
Potassium Channels, Inwardly Rectifying
Protein Structure, Tertiary
Receptors, Drug
Sulfonylurea Receptors