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

Abstract

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.

KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart

“…K ATP channels are tightly coupled with intracellular energetic networks (1,7,10,25,58), and metabolic signals of distress are the primary inductors of channel activity with pore opening associated with regulation of action potential duration (48,60). The property of signal decoding and translation of cellular energetic fluctuations implicates cardiac K ATP channels in the feedback regulation of membrane electrical activity (2,12). In conjunction with an intrinsic ATPase activity, the tandem function of nucleotide binding domains within the SUR2A regulatory subunit gates Kir6.2 (61), securing pore opening and action potential shortening in response to stress (33,60).…”

“…In conjunction with an intrinsic ATPase activity, the tandem function of nucleotide binding domains within the SUR2A regulatory subunit gates Kir6.2 (61), securing pore opening and action potential shortening in response to stress (33,60). The proposed role of a metabolic rheostat associated with preservation of energy economy (2,30) has prompted investigation to establish the contribution of K ATP channels in matching demands for homeostatic maintenance.…”

KCNJ11 knockout morula re-engineered by stem cell diploid aggregation

“…K ATP channels operate as high-fidelity molecular rheostats adjusting membrane potential-dependent functions to match cellular energetic demands (Terzic et al 1995;Alekseev et al 2005). Underscoring the critical role for K ATP channels in coupling metabolic dynamics with electrical activity is the recognition that disruption of channel function is life threatening (Ashcroft 2005;Reyes et al 2007).…”

“Roid-Rage” at the Cellular Level: Abolition of Endogenous Cardioprotection by Anabolic Steroids Reveals New Links Between the RAAS and Cardiac KATP Channels

“…sarcK ATP channels are highly expressed in the cardiac sarcolemma, and open in response to local changes in nucleotide content (reviewed in [2][3][4]). A growing body of literature supports a positive correlation between sarcK ATP expression and cardioprotection [5,6].…”