ATP-sensitive potassium (KATP) channels are bifunctional multimers assembled by an ion conductor and a sulfonylurea receptor (SUR) ATPase. Sensitive to ATP/ADP, KATP channels are vital metabolic sensors. However, channel regulation by competitive ATP/ADP binding would require oscillations in intracellular nucleotides incompatible with cell survival. We found that channel behavior is determined by the ATPase-driven engagement of SUR into discrete conformations. Capture of the SUR catalytic cycle in prehydrolytic states facilitated pore closure, while recruitment of posthydrolytic intermediates translated in pore opening. In the cell, channel openers stabilized posthydrolytic states promoting KATP channel activation. Nucleotide exchange between intrinsic ATPase and ATP/ADP-scavenging systems defined the lifetimes of specific SUR conformations gating KATP channels. Signal transduction through the catalytic module provides a paradigm for channel/enzyme operation and integrates membrane excitability with metabolic cascades.
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We are grateful to Dr. T.P. Burghardt and Dr. K. Ajtai for insightful discussions, and Dr. S. Seino, Dr. J. Bryan, and Dr. Y. Kurachi for K ATP channel clones. This work was supported by NIH (HL-64822, HL-07111), American Heart Association, Miami Heart Research Institute, American Physicians Fellowship for Medicine in Israel, Bruce and Ruth Rappaport Program in Vascular Biology and Gene Delivery, and the Marriott Foundation. A.T. is an Established Investigator of the American Heart Association.