Dependency of Calcium Alternans on Ryanodine Receptor Refractoriness
Alvarez-Lacalle, Enrique (Universitat Politècnica de Catalunya)
Cantalapiedra, Inma R. (Universitat Politècnica de Catalunya)
Peñaranda, Angelina (Universitat Politècnica de Catalunya)
Cinca, Juan (Institut d'Investigació Biomèdica Sant Pau)
Hove-Madsen, Leif (Institut d'Investigació Biomèdica Sant Pau)
Echebarria, Blas (Universitat Politècnica de Catalunya)
Universitat Autònoma de Barcelona. Departament de Medicina

Date:	2013
Abstract:	Background: Rapid pacing rates induce alternations in the cytosolic calcium concentration caused by fluctuations in calcium released from the sarcoplasmic reticulum (SR). However, the relationship between calcium alternans and refractoriness of the SR calcium release channel (RyR2) remains elusive. Methodology/Principal Findings: To investigate how ryanodine receptor (RyR2) refractoriness modulates calcium handling on a beat-to-beat basis using a numerical rabbit cardiomyocyte model. We used a mathematical rabbit cardiomyocyte model to study the beat-to-beat calcium response as a function of RyR2 activation and inactivation. Bi-dimensional maps were constructed depicting the beat-to-beat response. When alternans was observed, a novel numerical clamping protocol was used to determine whether alternans was caused by oscillations in SR calcium loading or by RyR2 refractoriness. Using this protocol, we identified regions of RyR2 gating parameters where SR calcium loading or RyR2 refractoriness underlie the induction of calcium alternans, and we found that at the onset of alternans both mechanisms contribute. At low inactivation rates of the RyR2, calcium alternans was caused by alternation in SR calcium loading, while at low activation rates it was caused by alternation in the level of available RyR2s. Conclusions/Significance: We have mapped cardiomyocyte beat-to-beat responses as a function of RyR2 activation and inactivation, identifying domains where SR calcium load or RyR2 refractoriness underlie the induction of calcium alternans. A corollary of this work is that RyR2 refractoriness due to slow recovery from inactivation can be the cause of calcium alternans even when alternation in SR calcium load is present. © 2013 Alvarez-Lacalle et al.
Grants:	Ministerio de Ciencia e Innovación FIS2008-06335-C02-01 Ministerio de Ciencia e Innovación FIS2011-28820-C02-01 Ministerio de Ciencia e Innovación FIS2009-13360-C03-03 Ministerio de Ciencia e Innovación SAF2011-30312 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-878
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Published in:	PloS one, Vol. 8 Núm. 2 (april 2013) , p. e55042, ISSN 1932-6203

DOI: 10.1371/journal.pone.0055042
PMID: 25540025
PMID: 23390511

11 p, 914.0 KB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
Articles > Research articles
Articles > Published articles