presentation/260 1st BioSim Conference - Presentation

1st BioSim Conference


Modelling and interpreting the consequences of Ca2+ influx via Na+/Ca2+ exchanger within T-tubules on SR release

Author: Anna Sher, Oxford University.

Names and affiliation of other authors:
Penelope J. Noble, Robert Hinch, David Gavaghan, Denis Noble

Oral or poster: Poster

It is well accepted that Na+/Ca2+ exchanger (NCX) in its forward mode regulates diastolic Ca2+ levels by extruding Ca2+ out of the cell. If NCXs are present in T-tubules and co-localized with ryanodine receptors (RyRs), then NCX may participate in Ca2+-induced Ca2+ release (CICR). The role of NCX during the initial upstroke of the action potential is controversial.
Our objective was to model NCXs within localized microdomains (dyads) where CICR occurs in order to interpret the functional significance of NCX protein presence within dyads on regulation of sarcoplasmic reticulum (SR) release. We developed a 15-state Makrov model that describes the joint behavior of L-type Ca2+ channels and RyRs. The key difference from previous models is the incorporation of local NCX current in both uniform and non-uniform fashion. The non-uniform distribution of NCXs among dyads is important in investigating the effects of drugs.
Our results were compared against the experimental data (e.g. Pott C. et al. In Press). Our simulations support a view that under physiological conditions NCX within T-tubules enables a relatively rapid and synchronous removal of Ca2+ throughout the cell.
Our model is a biophysically detailed tool for investigating the regulation of SR release via NCX and is well suited for incorporation in single cell models of ventricular myocardium. This work illustrates the importance of an interplay between modelling and experimental investigation in cardiovascular research.

Formatted version of the abstract or additional information

1st BioSim Conference. October 6th to October 8th, 2005. Palma de Mallorca, Spain.