Skip to main content
eScholarship
Open Access Publications from the University of California

A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+loading and CaMKII

  • Author(s): Morotti, S
  • Edwards, AG
  • Mcculloch, AD
  • Bers, DM
  • Grandi, E
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961080/
No data is associated with this publication.
Abstract

Ca2+-calmodulin-dependent protein kinase II (CaMKII) hyperactivity in heart failure causes intracellular Na+([Na+]i) loading (at least in part by enhancing the late Na+current). This [Na+]igain promotes intracellular Ca2+([Ca2+]i) overload by altering the equilibrium of the Na+-Ca2+exchanger to impair forward-mode (Ca2+extrusion), and favour reverse-mode (Ca2+influx) exchange. In turn, this Ca2+overload would be expected to further activate CaMKII and thereby form a pathological positive feedback loop of ever-increasing CaMKII activity, [Na+]i, and [Ca2+]i. We developed an ionic model of the mouse ventricular myocyte to interrogate this potentially arrhythmogenic positive feedback in both control conditions and when CaMKIIδC is overexpressed as in genetically engineered mice. In control conditions, simulation of increased [Na+]icauses the expected increases in [Ca2+]i, CaMKII activity, and target phosphorylation, which degenerate into unstable Ca2+handling and electrophysiology at high [Na+]igain. Notably, clamping CaMKII activity to basal levels ameliorates but does not completely offset this outcome, suggesting that the increase in [Ca2+]iper se plays an important role. The effect of this CaMKII-Na+-Ca2+-CaMKII feedback is more striking in CaMKIIδC overexpression, where high [Na+]icauses delayed afterdepolarizations, which can be prevented by imposing low [Na+]i, or clamping CaMKII phosphorylation of L-type Ca2+channels, ryanodine receptors and phospholamban to basal levels. In this setting, Na+loading fuels a vicious loop whereby increased CaMKII activation perturbs Ca2+and membrane potential homeostasis. High [Na+]iis also required to produce instability when CaMKII is further activated by increased Ca2+loading due to β-adrenergic activation. Our results support recent experimental findings of a synergistic interaction between perturbed Na+fluxes and CaMKII, and suggest that pharmacological inhibition of intracellular Na+loading can contribute to normalizing Ca2+and membrane potential dynamics in heart failure. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Item not freely available? Link broken?
Report a problem accessing this item