41 research outputs found
Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study
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