抄録
<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>I</jats:italic><jats:sub>f</jats:sub>) and ryanodine receptor-derived diastolic local subsarcolemmal Ca<jats:sup>2+</jats:sup> 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.</jats:p>
収録刊行物
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- Nature Communications
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Nature Communications 8 (1), 1258-, 2017-11-02
Springer Science and Business Media LLC