Download Stress without distress: homeostatic role for KATP channels

Molecular Psychiatry (2003) 8, 253–254
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NEWS & COMMENTARY
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,
News & Commentary
254
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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