CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current

Abstract The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (...

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Autores principales:	Futoshi Toyoda, Pietro Mesirca, Stefan Dubel, Wei-Guang Ding, Joerg Striessnig, Matteo E. Mangoni, Hiroshi Matsuura
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/31da581eaaa3446c8c655c6a488ae13e
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spelling	oai:doaj.org-article:31da581eaaa3446c8c655c6a488ae13e2021-12-02T15:06:25ZCaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current10.1038/s41598-017-08191-82045-2322https://doaj.org/article/31da581eaaa3446c8c655c6a488ae13e2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08191-8https://doaj.org/toc/2045-2322Abstract The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (I st), a key player in SAN automaticity, is still unknown. Here we show that I st and the L-type Ca2+ current (I Ca,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that I st is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to I Ca,L activators and blockers. Both CaV1.3-mediated I Ca,L and I st were abolished in CaV1.3-deficient (CaV1.3−/−) SAN cells but the CaV1.2-mediated I Ca,L current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive CaV1.2 channels (CaV1.2DHP−/−), I st and CaV1.3-mediated I Ca,L displayed overlapping sensitivity and concentration–response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies I st, a considerable fraction of I Ca,L was resistant to nifedipine inhibition in CaV1.2DHP−/− SAN cells. These findings identify CaV1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive I st Na+ current in the SAN.Futoshi ToyodaPietro MesircaStefan DubelWei-Guang DingJoerg StriessnigMatteo E. MangoniHiroshi MatsuuraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Futoshi Toyoda Pietro Mesirca Stefan Dubel Wei-Guang Ding Joerg Striessnig Matteo E. Mangoni Hiroshi Matsuura CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current
description	Abstract The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (I st), a key player in SAN automaticity, is still unknown. Here we show that I st and the L-type Ca2+ current (I Ca,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that I st is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to I Ca,L activators and blockers. Both CaV1.3-mediated I Ca,L and I st were abolished in CaV1.3-deficient (CaV1.3−/−) SAN cells but the CaV1.2-mediated I Ca,L current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive CaV1.2 channels (CaV1.2DHP−/−), I st and CaV1.3-mediated I Ca,L displayed overlapping sensitivity and concentration–response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies I st, a considerable fraction of I Ca,L was resistant to nifedipine inhibition in CaV1.2DHP−/− SAN cells. These findings identify CaV1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive I st Na+ current in the SAN.
format	article
author	Futoshi Toyoda Pietro Mesirca Stefan Dubel Wei-Guang Ding Joerg Striessnig Matteo E. Mangoni Hiroshi Matsuura
author_facet	Futoshi Toyoda Pietro Mesirca Stefan Dubel Wei-Guang Ding Joerg Striessnig Matteo E. Mangoni Hiroshi Matsuura
author_sort	Futoshi Toyoda
title	CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current
title_short	CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current
title_full	CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current
title_fullStr	CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current
title_full_unstemmed	CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current
title_sort	cav1.3 l-type ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent na+ current
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/31da581eaaa3446c8c655c6a488ae13e
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CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current

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