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Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling

Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that in...

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Autores principales: Lin, Richard Z., Lu, Zhongju, Anyukhovsky, Evgeny P., Jiang, Ya-Ping, Wang, Hong Zhan, Gao, Junyuan, Rosen, Michael R., Ballou, Lisa M., Cohen, Ira S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683667/
https://www.ncbi.nlm.nih.gov/pubmed/31217223
http://dx.doi.org/10.1085/jgp.201812293
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author Lin, Richard Z.
Lu, Zhongju
Anyukhovsky, Evgeny P.
Jiang, Ya-Ping
Wang, Hong Zhan
Gao, Junyuan
Rosen, Michael R.
Ballou, Lisa M.
Cohen, Ira S.
author_facet Lin, Richard Z.
Lu, Zhongju
Anyukhovsky, Evgeny P.
Jiang, Ya-Ping
Wang, Hong Zhan
Gao, Junyuan
Rosen, Michael R.
Ballou, Lisa M.
Cohen, Ira S.
author_sort Lin, Richard Z.
collection PubMed
description Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, I(F), while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of I(F) are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias.
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spelling pubmed-66836672020-02-05 Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling Lin, Richard Z. Lu, Zhongju Anyukhovsky, Evgeny P. Jiang, Ya-Ping Wang, Hong Zhan Gao, Junyuan Rosen, Michael R. Ballou, Lisa M. Cohen, Ira S. J Gen Physiol Research Articles Heart rate in physiological conditions is set by the sinoatrial node (SN), the primary cardiac pacing tissue. Phosphoinositide 3-kinase (PI3K) signaling is a major regulatory pathway in all normal cells, and its dysregulation is prominent in diabetes, cancer, and heart failure. Here, we show that inhibition of PI3K slows the pacing rate of the SN in situ and in vitro and reduces the early slope of diastolic depolarization. Furthermore, inhibition of PI3K causes a negative shift in the voltage dependence of activation of the pacemaker current, I(F), while addition of its second messenger, phosphatidylinositol 3,4,5-trisphosphate, induces a positive shift. These shifts in the activation of I(F) are independent of, and larger than, those induced by the autonomic nervous system. These results suggest that PI3K is an important regulator of heart rate, and perturbations in this signaling pathway may contribute to the development of arrhythmias. Rockefeller University Press 2019-08-05 2019-06-19 /pmc/articles/PMC6683667/ /pubmed/31217223 http://dx.doi.org/10.1085/jgp.201812293 Text en © 2019 Lin et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Lin, Richard Z.
Lu, Zhongju
Anyukhovsky, Evgeny P.
Jiang, Ya-Ping
Wang, Hong Zhan
Gao, Junyuan
Rosen, Michael R.
Ballou, Lisa M.
Cohen, Ira S.
Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling
title Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling
title_full Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling
title_fullStr Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling
title_full_unstemmed Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling
title_short Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling
title_sort regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683667/
https://www.ncbi.nlm.nih.gov/pubmed/31217223
http://dx.doi.org/10.1085/jgp.201812293
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