Mammalian γ2 AMPK regulates intrinsic heart rate.
Nat Commun
; 8(1): 1258, 2017 11 02.
Article
em En
| MEDLINE
| ID: mdl-29097735
ABSTRACT
AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αßγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 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 Ca2+ release. In contrast, loss of γ2 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Sarcolema
/
Nó Sinoatrial
/
Bradicardia
/
Cálcio
/
Proteínas Quinases Ativadas por AMP
/
Frequência Cardíaca
Limite:
Adult
/
Animals
/
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article