Kir6.2 is required for adaptation to stress

Abstract

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (KATP) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted KATP channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for KATP channels in the heart. I on channels control the electrical potential across the cell membrane of all living organisms. The profile of channel expression within the cell is defined by evolution through natural selection (1, 2). Developed as channel͞enzyme multimers, K ATP channels combine properties of two different classes of protein to adjust rapidly and precisely membrane excitability according to the metabolic state of the cell (3-7). Identified in metabolically active tissues of a broad range of species, K ATP channels were discovered originally in heart muscle where they are expressed in high density (8, 9). Functional cardiac K ATP channels can be formed only through physical association of the pore-forming Kir6.2 subunit with the regulatory sulfonylurea receptor SUR2A (10-12). In this complex, which harbors an intrinsic ATPase activity, nucleotide interaction at SUR2A gates potassium permeation through Kir6.2, a property believed to be responsible for the fine metabolic modulation of membrane potential-dependent cellular functions (7,(13)(14)(15)(16).The physiological role of K ATP channels as metabolic sensors has been understood best in the regulation of hormone secretion in pancreatic ␤-cells and more recently in the hypothalamus (17-21). In the heart, definition of the function of this protein complex thus far has been limited to acute protection against ischemic events (22). In fact, under ischemia, the opening of as few as 1% of K ATP channels is sufficient to produce significant shortening of the cardiac action potential (23), manifested globally by ST-segment elevation on the electrocardiogram (24). Yet, beyond the impact in pathophysiology, a physiological role for the cardiac K ATP channel that supports its maintenance in hearts of many species is lacking (25).The general adaptation syndrome is a ubiquitous reaction vital for self-preservation under conditions of stress such as exertion or fear (26-28). Mediated by a catecholamine surge, this syndrome generates an alteration of physiologic and biochemical functions to sustain a superior level of bodily performance and allows confrontation or escape in response to threat...

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

“…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 Ca 2+ 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].…”

“…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].…”

Potassium channels in the sinoatrial node and their role in heart rate control

“…Kir6.2 is thought to underlie the classic current present in pancreatic β cells and ventricular cardiomyocytes [87]. Kir6.2 global knockout mice are unable to tolerate high intensity exercise partly due to impaired cardiac performance [88]. …”