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Publication : Mammalian γ2 AMPK regulates intrinsic heart rate.

First Author  Yavari A Year  2017
Journal  Nat Commun Volume  8
Issue  1 Pages  1258
PubMed ID  29097735 Mgi Jnum  J:256296
Mgi Id  MGI:6106252 Doi  10.1038/s41467-017-01342-5
Citation  Yavari A, et al. (2017) Mammalian gamma2 AMPK regulates intrinsic heart rate. Nat Commun 8(1):1258
abstractText  AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as alphabetagamma complexes, whose regulatory gamma subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the gamma2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that gamma2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca(2+) release. In contrast, loss of gamma2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.
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