Mammalian γ2 AMPK regulates intrinsic heart rate.
Mammalian γ2 AMPK regulates intrinsic heart rate.
复制标题
DOI：
10.1038/s41467-017-01342-5
复制
发表时间：
2017-11-02
影响因子：
16.6
通讯作者：
Ashrafian H
中科院分区：
文献类型：
--
作者：
Yavari 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
AMPK是一种保守的丝氨酸/苏氨酸激酶，其活性维持细胞能量稳态。真核生物AMPK以αβγ复合物的形式存在，其调节性γ亚基通过与腺嘌呤核苷酸结合而赋予能量传感器功能。携带γ2亚基激活突变的人表现出包括无法解释的心率减慢（心动过缓）的表型。在这里，我们发现γ2 AMPK激活下调基本的窦房细胞起搏机制，以降低心率，包括肌膜超极化激活电流（I f）和ryanodine受体衍生的舒张期局部肌膜下Ca 2+释放。相反，γ2 AMPK的缺失诱导心率增加的相互表型，并阻止耐力训练的适应性内在心动过缓。我们的研究结果表明，在哺乳动物中，心率是心脏能量需求的关键决定因素，AMPK以器官特异性方式发挥作用，以维持心脏能量稳态，并通过调节固有的窦房细胞行为来决定心脏对运动的生理适应。AMPK通过其γ亚基作为细胞AMP和ADP/ATP比值的能量传感器调节细胞能量平衡。在这里，作者表明，γ2 AMPK激活通过降低起搏细胞的活性来降低心率，而γ2 AMPK的丧失会增加心率并防止小鼠耐力训练的适应性心动过缓。
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. AMPK regulates cellular energy balance using its γ subunit as an energy sensor of cellular AMP and ADP to ATP ratios. Here, the authors show that γ2 AMPK activation lowers heart rate by reducing the activity of pacemaker cells, whereas loss of γ2 AMPK increases heart rate and prevents the adaptive bradycardia of endurance training in mice.
登录
查看更多内容
DOI：
10.1152/ajpendo.00237.2016
发表时间：
2016-10-01
期刊：
American journal of physiology. Endocrinology and metabolism
影响因子：
--
作者：
Bultot L;Jensen TE;Lai YC;Madsen AL;Collodet C;Kviklyte S;Deak M;Yavari A;Foretz M;Ghaffari S;Bellahcene M;Ashrafian H;Rider MH;Richter EA;Sakamoto K
通讯作者：
Sakamoto K
影响因子：
4.1
作者：
Cheung, PCF;Salt, IP;Carling, D
通讯作者：
Carling, D
影响因子：
5.5
作者：
Danson, EJF;Paterson, DJ
通讯作者：
Paterson, DJ
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J
影响因子：
--
作者：
Folmes, Karalyn D.;Chan, Anita Y. M.;Dyck, Jason R. B.
通讯作者：
Dyck, Jason R. B.