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.

Introduction

ATP-sensitive K⁺ (K_ATP) channels are molecular combinations of an inwardly rectifying K⁺ channel, Kir6.x, and a regulatory module, the sulfonylurea receptor SUR [1], [2], [3]. Biogenesis of the heteromultimeric K_ATP channel occurs through combinations of subunit isoforms that define the intrinsic properties and tissue specificity of the channel complex [3], [4]. Physical association of the Kir6.2 and SUR2A isoforms generates cardiac K_ATP channels that are expressed in high density at the sarcolemma [5], [6]. By virtue of their integration with cellular energetic networks and their ability to decode metabolic signals, K_ATP channels set membrane excitability to match demand for homeostatic maintenance [7], [8], [9], [10], [11]. Recent progress in the understanding of K_ATP channel structure and function has been founded on the dissection of channel subunit properties, mapping of channel coupling with cellular energetics and definition of the metabolic sensing role in both healthy and diseased cells.

Under conditions of metabolic surplus, the cardiac K_ATP channel responds by closure while metabolic challenge provokes channel opening with consequent K⁺ efflux, action potential shortening, and limitation of potentially damaging intracellular Ca²⁺ loading [10], [12], [13]. The basic gating of the K_ATP channel that underlies the channel's metabolic response occurs in reaction to the balance at the channel site of inhibitory and stimulatory nucleotides, ATP and ADP, respectively [1], [14]. The way in which the cellular metabolic state is “read” incorporates generation and delivery of nucleotide signals to the K_ATP channel subunits, and nucleotide interactions with specialized channel domains that ultimately secure signal processing and translation into pore gating [15], [16].

In this way, K_ATP channels mediate a homeostatic membrane response to the metabolic insults of ischemia or hypoxia contributing to a cardioprotective outcome [17], [18]. Recent studies indicate an even broader function for cardiac K_ATP channels in the tolerance of cardiomyocytes to numerous acute and chronic metabolic challenges, including sympathetic surge, and physical training [10], [19]. Furthermore, the concept of K_ATP channel-mediated myocardial protection has been expanded to include balancing increased performance to meet augmented demands of stress while avoiding an excessive response that could result in cellular injury and/or arrhythmia [10], [19], [20], [21]. The homeostatic role of K_ATP channels is underscored by studies of altered channel behavior in heart disease. Channel gene mutations that disrupt K_ATP channel function [14] and/or defects in signaling pathways proximal to the channel site [20] compromise the channel's ability to optimally respond to metabolic challenge. Thus, proper metabolic gating of K_ATP channels is vital in limiting acute adverse myocardial outcomes under stress, and in evading injury that precipitates the development or progression of chronic heart disease [10], [11], [14], [19], [20].