Nature communications · 2017

Mammalian γ2 AMPK regulates intrinsic heart rate.

СтатьяResearch Support, N.I.H., IntramuralПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

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Yavari Arash, Bellahcene Mohamed, Bucchi Annalisa, Sirenko Syevda, Pinter Katalin, Herring Neil, Jung Julia J, Tarasov Kirill V, Sharpe Emily J, Wolfien Markus, Czibik Gabor, Steeples Violetta, Ghaffari Sahar, Nguyen Chinh, Stockenhuber Alexander, Clair Joshua R St, Rimmbach Christian, Okamoto Yosuke, Yang Dongmei, Wang Mingyi, Ziman Bruce D, Moen Jack M, Riordon Daniel R, Ramirez Christopher, Paina Manuel, Lee Joonho, Zhang Jing, Ahmet Ismayil, Matt Michael G, Tarasova Yelena S, Baban Dilair, Sahgal Natasha, Lockstone Helen, Puliyadi Rathi, de Bono Joseph, Siggs Owen M, Gomes John, Muskett Hannah, Maguire Mahon L, Beglov Youlia, Kelly Matthew, Dos Santos Pedro P N, Bright Nicola J, Woods Angela, Gehmlich Katja, Isackson Henrik, Douglas Gillian, Ferguson David J P, Schneider Jürgen E, Tinker Andrew, Wolkenhauer Olaf, Channon Keith M, Cornall Richard J, Sternick Eduardo B, Paterson David J, Redwood Charles S, Carling David, Proenza Catherine, David Robert, Baruscotti Mirko, DiFrancesco Dario, Lakatta Edward G, Watkins Hugh, Ashrafian Houman

Аннотация

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 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.

Mammalian γ2 AMPK regulates intrinsic heart rate.

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