Mammalian γ2 AMPK regulates intrinsic heart rate.
1258 - ?
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AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ 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 Ca(2+) 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.
AuthorsYavari, A; Bellahcene, M; Bucchi, A; Sirenko, S; Pinter, K; Herring, N; Jung, JJ; Tarasov, KV; Sharpe, EJ; Wolfien, M; Czibik, G; Steeples, V; Ghaffari, S; Nguyen, C; Stockenhuber, A; Clair, JRS; Rimmbach, C; Okamoto, Y; Yang, D; Wang, M; Ziman, BD; Moen, JM; Riordon, DR; Ramirez, C; Paina, M; Lee, J; Zhang, J; Ahmet, I; Matt, MG; Tarasova, YS; Baban, D; Sahgal, N; Lockstone, H; Puliyadi, R; de Bono, J; Siggs, OM; Gomes, J; Muskett, H; Maguire, ML; Beglov, Y; Kelly, M; Dos Santos, PPN; Bright, NJ; Woods, A; Gehmlich, K; Isackson, H; Douglas, G; Ferguson, DJP; Schneider, JE; Tinker, A; Wolkenhauer, O; Channon, KM; Cornall, RJ; Sternick, EB; Paterson, DJ; Redwood, CS; Carling, D; Proenza, C; David, R; Baruscotti, M; DiFrancesco, D; Lakatta, EG; Watkins, H; Ashrafian, H
- Cardiovascular