Cardiac Atp-sensitive Potassium Channel: A Bi-functional Channel/enzyme Multimer

摘要

Summary. Maintenance of myocardial homeostasis critically depends on the ability of cardiac cells to adapt energy-dependent processes in response to metabolic challenge. This requires efficient monitoring of the cellular energetic status, secure delivery of information to energetic sensors and accurate translation of metabolic signals into cellular response. Although advances have been made in resolving the molecular identity of energy-response elements, mechanisms integrating metabolic sensor function with cellular metabolism are largely unknown. Sarcolemmal ATP-sensitive K+ (KATP) channels are prototypic membrane metabolic sensors, which act as bi-functional protein multimers combining catalytic with ion conduction properties. In the hetero-octameric KATi channel complex, the sulfonylurea receptor (SUR2A) harbors an intrinsic ATPase activity and confers fine nucleotide modulation of K+ permeation through the pore-forming Kir6.2 subunit. The metabolic sensor role of K channels stems from the non-equivalent properties of nucleotide binding domains (NBD1 and NBD2) in SUR2A. NBD1 binds nudeotides whereas NBD2 hydrolyzes ATP, yet cooperative interaction, rather than the independent contribution of each NBD, is critical for KATp channel regulation. The ATP hydrolysis cycle at SUR2A drives conformational transitions with distinct outcomes on channel gating to adjust membrane potential in response to intra-cellular metabolic oscillations. Nucleotide exchange between the channel ATPase and the cellular phosphotransfer network provides a mechanistic basis for coupling cell energetics with K_ATP channel gating.