Stress without distress: homeostatic role for KATP channels - Nature

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tary–adrenal axis and autonomic nervous system.1. This ubiquitous response underlies the 'fight-or- flight' reaction by alteration of bodily functions to sustain a ...
Molecular Psychiatry (2003) 8, 253–254 & 2003 Nature Publishing Group All rights reserved 1359-4184/03 $25.00 www.nature.com/mp

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Stress without distress: homeostatic role for KATP channels Molecular Psychiatry (2003) 8, 253–254. doi:10.1038/ sj.mp.4001323

Stress is defined as a threat, real or implied, to the narrow range of physiological parameters necessary for survival, with the dynamic of existence comprising an ongoing sequence of stressful events and their consequences.1 Self-preservation is achieved through the general adaptation syndrome that is initiated by brain recognition of threat leading to modification of behavior and activation of the hypothalamic-pituitary–adrenal axis and autonomic nervous system.1 This ubiquitous response underlies the ‘fight-orflight’ reaction by alteration of bodily functions to sustain a new performance level necessary for confrontation or evasion of threatening conditions.1 However, augmentation in performance is metabolically demanding, and requires a safety mechanism to prevent fatal exhaustion of resources. Recently, the ATP-sensitive potassium (KATP) channel, a cell membrane metabolic sensor, was identified as a critical component in maintaining the body’s homeostasis during the adaptive reaction to stress, such that the reaction itself does not become deleterious to the organism.2 KATP channels, widely represented in metabolically active tissues, are formed through physical association of the pore-forming inwardly rectifying potassium channel, Kir6.x, with the regulatory sulfonylurea receptor, SUR.3 In this way, Kir6.2 and SUR2A generate cardiac and skeletal muscle KATP channels.4 Metabolic sensing occurs through modulation of Kir6.2 ATP-sensitivity by the SUR2A subunit ATPase activity such that stabilization of SUR2A in a posthydrolytic state favors K þ efflux through Kir6.2 leading to membrane hyperpolarization.5 These intrinsic channel properties, along with tight integration of KATP channel proteins with cellular metabolic pathways, are responsible for the rapid and precise metabolic modulation of membrane potential-dependent cellular functions.5 Vascular smooth muscle channels combine Kir6.1 and SUR2B,6 and channels in pancreatic b-cells comprise Kir6.2 and SUR1.3 In neurons, various permutations of Kir6.1 or Kir6.2 and SUR1 or SUR2 coexpression form KATP channels.7 Such structural diversity defines a wide spectrum of KATP channel involvement in tissue-specific funcCorrespondence: Dr A Terzic, Guggenheim 7, Mayo Clinic, Rochester, MN 55905, USA. E-mail: [email protected]

tions, yet the underlying property of the metabolic mediator remains consistent. In the heart, while the role of KATP channels has been viewed as that of protection against the metabolic insult of ischemic injury, recent data support a broader interpretation of these channels as molecular mediators in the adaptive response to stress.2 Indeed, under exercise-stress, a natural trigger of the general adaptation syndrome,1 mice lacking KATP channels through genetic deletion of Kir6.2 perform at a significantly reduced level than age- and gendermatched normal controls.2 In stress situations, sympathetic stimulation augments cardiac output to support the body’s immediate or anticipated requirement of enhanced performance. This augmented work imposes a significant demand on cardiac metabolic resources, mostly because of energy-consuming Ca2 þ handling. To prevent cellular Ca2 þ overload and associated energy depletion, increased Ca2 þ influx is normally balanced by a compensatory increase in outward potassium ion currents. This protective feedback mechanism is absent in myocardium lacking KATP channels.2 Hearts from Kir6.2-knockout mice display less shortening of the action potential after adrenoreceptor stimulation than normal hearts. In fact, Kir6.2-knockout mice demonstrate a phenotype of increased vulnerability under stress manifested by aberrant regulation of cardiac membrane excitability, inadequate calcium handling, and fatal ventricular arrhythmia.2 This underscores the vital role of KATP channels in the coordination of cardiac function with changing metabolic conditions. Moreover, KATP channels regulate vascular tone, and thereby the delivery of metabolic resources to match demand.8 Furthermore, these channels are central in setting blood glucose levels by regulating insulin exocytosis in pancreatic b-cells and insulindependent glucose uptake in skeletal muscle.3,9–12 Thus, KATP channels adjust the function of endorgan systems critical in the adaptive response to stress. Ultimately in the hierarchy of the general adaptation syndrome, KATP channels in the nervous system operate via changes in neuronal excitability as a feedback mechanism coupling the adaptive response to the metabolic state.7,13,14 In particular, KATP channel activity defines the firing rate of glucose-responsive neurons identified in a number of discrete brain areas including the ventromedial, arcuate and paraventricular nuclei of the hypothalamus, substantia nigra, as well as in the area postrema and the tractus solitarius nucleus.7,13–15 When extracellular glucose increases,

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in response to neuroglycopenia and hypoglycemia.14 Further, KATP channels have been implicated in the control of satiety and pain perception.7,15 Thus, the KATP channel/enzyme protein complex, integrated with cellular and systemic metabolism, acts at various levels to ensure energetic homeostasis under the augmented functional demands of the adaptation reaction (Figure 1). In this way, the KATP channel serves as a unifying molecular coordinator of metabolic well-being under stress. This homeostatic function identifies the role of KATP channels in the hierarchy of molecular events underlying propagation of the general adaptation syndrome.

Acknowledgements Figure 1 KATP channels maintain balance between the adaptive response to stress and metabolic resources to ensure survival. KATP channels, comprised of the poreforming Kir6.x and regulatory SUR subunits, are represented in metabolically active tissues where they support execution of the general adaptation syndrome under stress and allocation of resources to balance the need for escape or confrontation with prevention of metabolic exhaustion. In this way the KATP channel, with a broad range of tissuespecific properties, acts as a unifying molecular coordinator of the body’s response to stress.

glucose metabolism in neurons promotes KATP channel inhibition leading to membrane depolarization and increased neuronal activity. Conversely, with the decrease in extracellular glucose levels, ensuing changes in cellular metabolism favor KATP channel opening associated with a reduced rate of neuronal firing. KATP channels are gated not only in response to oscillations in extracellular glucose, but also respond to the direct action of stress-sensitive neuromediators, including endorphins, adenosine and leptin.15 Changes in neuronal activity translate into modification of the adaptive response through behavioral effects, and activation patterns of the hypothalamicpituitary–adrenal axis. Kir6.2-knockout mice exhibit a severe defect in hypothalamic-pituitary–adrenal axis-dependent glucagon secretion and food intake

Molecular Psychiatry

The authors are supported by the National Institutes of Health, American Heart Association, Marriott Foundation, Miami Heart Research Institute, Bruce and Ruth Rappaport Program, and the American Physicians Fellowship for Medicine in Israel. AT is an Established Investigator of the American Heart Association. LV Zingman, DM Hodgson, AE Alekseev and A Terzic Departments of Medicine and Molecular Pharmacology and Experimental Therapeutics, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, USA

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