The reconstructed geometry that was used to model local calcium handling in cardiac myocytes: t-tubule [blue], SR [yellow/orange], Mitochondria [violet].

COMPUTATIONAL MODELING OF LOCAL CALCIUM HANDLINE IN CARDIAC MYOCYTES

Jerry Tsai, PRIME 2011 (Australia)

A calcium spark is the fundamental unit of calcium release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling, and it is the major contributor to the diastolic calcium leak in cardiomyocytes. The duration and magnitude of the spark is determined by the local geometry of a single calcium release unit (CRU) as well as the locality and density of calcium handling proteins. We have developed a detailed computational model of a single CRU situated in its native cellular environment (see Figure). Calcium diffusion is modeled both within the SR and the cytosol. The model includes several unknown parameters, such as the diffusion constant of calcium within SR and the conductance of the CRU, which needed to be fitted to data from Zima, et al. (in the September 2008 edition of the journal Circulation Research, in an article titled “Termination of Cardiac Ca2+ Sparks”).

I used the Nimrod system on a 220-core cluster at Monash University to fit the unknown parameters. We then proceeded to investigate the effect of different locations of calcium handling protein close to the release unit. We found that the sarco-endoplasmic reticulum calcium ATPase (SERCA) pump affects the duration of the release by pumping already-released calcium back into the SR. I also found that using a simplistic model of the sodium/calcium exchanger on the cell membrane inside the CRU does not work as it drains calcium out of the cell before it can trigger contraction. These findings will help us to better understand what regulates the size and duration of a single calcium spark.

PARTICIPATING RESEARCHERS: Monash University: David Abramson, Blair Bethwaite; UCSD: Johan E. Hake

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