Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study
| dc.citation.issueNumber | 54 | |
| dc.citation.journalTitle | Theoretical Biology and Medical Modelling | |
| dc.citation.volumeNumber | 10 | |
| dc.contributor.author | Krishna, Abhilash | |
| dc.contributor.author | Valderrábano, Miguel | |
| dc.contributor.author | Palade, Philip T. | |
| dc.contributor.author | Clark, John W. Jr. | |
| dc.date.accessioned | 2013-09-25T17:44:52Z | |
| dc.date.available | 2013-09-25T17:44:52Z | |
| dc.date.issued | 2013-09-10 | |
| dc.description.abstract | Rate-dependent effects on the Ca2+ sub-system in a rat ventricular myocyte are investigated. Here, we employ a deterministic mathematical model describing various Ca2+ signalling pathways under voltage clamp (VC) conditions, to better understand the important role of calmodulin (CaM) in modulating the key control variables Ca2+/calmodulin-dependent protein kinase-II (CaMKII), calcineurin (CaN), and cyclic adenosine monophosphate (cAMP) as they affect various intracellular targets. In particular, we study the frequency dependence of the peak force generated by the myofilaments, the force-frequency response (FFR). Our cell model incorporates frequency-dependent CaM-mediated spatially heterogenous interaction of CaMKII and CaN with their principal targets (dihydropyridine (DHPR) and ryanodine (RyR) receptors and the SERCA pump). It also accounts for the rate-dependent effects of phospholamban (PLB) on the SERCA pump; the rate-dependent role of cAMP in up-regulation of the L-type Ca2+ channel (ICa;L); and the enhancement in SERCA pump activity via phosphorylation of PLB.Our model reproduces positive peak FFR observed in rat ventricular myocytes during voltage-clamp studies both in the presence/absence of cAMP mediated -adrenergic stimulation. This study provides quantitative insight into the rate-dependence of Ca2+-induced Ca2+-release (CICR) by investigating the frequency-dependence of the trigger current (ICa;L) and RyR-release. It also highlights the relative role of the sodium-calcium exchanger (NCX) and the SERCA pump at higher frequencies, as well as the rate-dependence of sarcoplasmic reticulum (SR) Ca2+ content. A rigorous Ca2+ balance imposed on our investigation of these Ca2+ signalling pathways clarifies their individual roles. Here, we present a coupled electromechanical study emphasizing the rate-dependence of isometric force developed and also investigate the temperature-dependence of FFR. Our model provides mechanistic biophysically based explanations for the rate-dependence of CICR, generating useful and testable hypotheses. Although rat ventricular myocytes exhibit a positive peak FFR in the presence/absence of beta-adrenergic stimulation, they show a characteristic increase in the positive slope in FFR due to the presence of Norepinephrine or Isoproterenol. Our study identifies cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of ICa;L as the key mechanisms underlying the aforementioned positive FFR. | |
| dc.identifier.citation | A. Krishna, M. Valderrábano, P. T. Palade and J. W. J. Clark, "Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study," <i>Theoretical Biology and Medical Modelling,</i> vol. 10, no. 54, 2013. | |
| dc.identifier.doi | http://dx.doi.org/10.1186/1742-4682-10-54 | |
| dc.identifier.uri | https://hdl.handle.net/1911/72114 | |
| dc.language.iso | eng | |
| dc.publisher | BioMed Central | |
| dc.title | Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study | |
| dc.type | Journal article | |
| dc.type.dcmi | Text | |
| dc.type.dcmi | Text |