Kir6.2 is required for adaptation to stress.
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 (K(ATP)) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted K(ATP) 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 K(ATP) channels in the heart.
Zingman
Leonid V
LV
Division of Cardiovascular Diseases, Departments of Medicine and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Hodgson
Denice M
DM
Bast
Peter H
PH
Kane
Garvan C
GC
Perez-Terzic
Carmen
C
Gumina
Richard J
RJ
Pucar
Darko
D
Bienengraeber
Martin
M
Dzeja
Petras P
PP
Miki
Takashi
T
Seino
Susumu
S
Alekseev
Alexey E
AE
Terzic
Andre
A
D000220:Adaptation, Biological; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D003645:Death, Sudden; D004594:Electrophysiology; D006439:Hemodynamics; D006706:Homeostasis; D007477:Ions; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010477:Perfusion; D010805:Physical Conditioning, Animal; D005082:Physical Exertion; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics* / Q000502:physiology*; D013312:Stress, Physiological; D013997:Time Factors
D007477:Ions; D024661:Potassium Channels, Inwardly Rectifying; D002118:Calcium