ATP-sensitive K+ channel channel/enzyme multimer:: Metabolic gating in the heart

Cardiac ATP-sensitive K+ (K-ATP) channels, gated by cellular metabolism, are formed by association of the inwardly rectifying potassium channel Kir6.2, the potassium conducting Subunit, and SUR2A, the ATP-binding cassette protein that serves as the regulatory subunit. Kir6.2 is the principal site of ATP-induced channel inhibition, while SUR2A regulates K+ flux through adenine nucleotide binding and catalysis. The ATPase-driven conformations within the regulatory SUR2A subunit of the K-ATP channel complex have determinate linkage with the states of the channel's pore. The probability and life-time of ATPase-induced SUR2A intermediates, rather than competitive nucleotide binding alone, defines nucleotide-dependent K-ATP channel gating. Cooperative interaction, instead of independent contribution of individual nucleotide binding domains within the SUR2A subunit, serves a decisive role in defining K-ATP channel behavior. Integration of K-ATP channels with the cellular energetic network renders these channel/enzyme heteromultimers high-fidelity metabolic sensors. This vital function is facilitated through phosphotransfer enzyme-mediated transmission of controllable energetic signals. By virtue of coupling with cellular energetic networks and the ability to decode metabolic signals, K-ATP channels set membrane excitability to match demand for homeostatic maintenance. This new paradigm in the operation of an ion channel multimer is essential in providing the basis for K-ATP channel function in the cardiac cell, and for understanding genetic defects associated with life-threatening diseases that result from the inability of the channel complex to optimally fulfill its physiological role (c) 2005 Elsevier Ltd. All rights reserved.