Journal article
Mammalian γ2 AMPK regulates intrinsic heart rate
- Abstract:
- 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 (If) and ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ releases. 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, where heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ specific manner to maintain cardiac energy homeostasis and determine cardiac physiological adaptation to exercise, by modulating intrinsic sinoatrial cell behaviour.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Publisher copy:
- 10.1038/s41467-017-01342-5
Authors
- Publisher:
- Nature Publishing Group
- Journal:
- Nature Communications More from this journal
- Volume:
- 8
- Pages:
- 1258
- Publication date:
- 2017-11-01
- Acceptance date:
- 2017-09-08
- DOI:
- ISSN:
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2041-1723
- Pubs id:
-
pubs:734928
- UUID:
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uuid:0716bea9-efa7-4fda-b74d-857547eedaa3
- Local pid:
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pubs:734928
- Deposit date:
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2017-10-10
- ARK identifier:
Terms of use
- Copyright holder:
- Yavari et al
- Copyright date:
- 2017
- Notes:
- © The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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