⇒ Ca2+ signaling system
We study the Ca2+ signaling system in cardiac myocytes to discover fundament properties and diseases mechanisms. We did extensive studies on the RyR organization and function that are important to excitation-contraction coupling.
The sarcomere is the basic unit of contraction in heart muscle. On every heartbeat Ca2+ flows out of the intracellular Ca2+ storage site (sarcoplasmic reticulum, SR) through ryanodine receptors (RyRs) arrayed at each end of the sarcomere. The figure shows the RyRs in a ventricular myocyte labeled by fluorescence-tagged antibody; the longitudinal striations, spaced ~2 μm apart, demarcate the sarcomeres. Ryanodine receptors are Ca2+ conducting channels that have a positive feedback gating mechanism: the RyR open probability increases as the cytosolic Ca2+ concentration rises, and the RyR opening allows massive Ca2+ release from SR to further increase the cytosolic Ca2+; then Ca2+ diffuses to the neighboring RyRs to increase their open probability, which releases more Ca2+. It is useful to think of the ryanodine receptors as piles of gunpowder. If the neighboring gunpowder piles are close together and enough heat is released then the piles will ignite one another in a spreading wave.
Combined Experiment-Modeling Studies
- We conducted experimental study to precisely measure 3-D distribution of the ryanodine receptors in cardiac myocytes.
- We developed mathematical models using the experimentally measured data to simulate Ca2+ waves generated by Ca2+ release through RyRs in cardiac myocytes.
|Model simulation of Ca2+ sparks & wave generation
- Chen-Izu Y*, Chris W. Ward, Wayne Stark Jr., Marius P. Sumandea, C. William Balke, Leighton T. Izu. Xander H.T. Wehrens. Phosphorylation of RyR2 and shortening of RyR2 cluster spacing in spontaneously hypertensive rat with heart failure. Am J Physiol. 293(4):H2409-17 (2007).
- Izu LT*, Banyasz T, Balke CW and Chen-Izu Y. Eavesdropping on the Social Lives of Ca2+ Sparks. Biophysical J 93:3408-3420 (2007) PMC2072070.
- Chen-Izu Y*, Stacey L. McCulle, Chris W. Ward, Christian Soeller, Bryan M Allen, Cal Rabang, Mark B Cannell, C William Balke, Leighton T. Izu*. Three-dimensional Distribution of Ryanodine Receptor Clusters in Cardiac Myocytes. Biophysical J 91:1-13 (2006) PMCID: PMC 1479079.
- Leighton T Izu*, Shawn Means, John Shadid, Chen-Izu Y, C. W. Balke. Interplay of Ryanodine Receptor Distribution and Calcium dynamics. Biophysical J 91:95-112 (2006) PMCID: PMC 1479049.
- Izu, L.T., J.R.H. Mauban, C.W. Balke, and W.G. Wier (2001). Large currents generate Ca2+ sparks. Biophys. J. 80:88-102.
- Izu, L.T., W.G. Wier, and C.W. Balke (2001). Evolution of cardiac calcium waves from stochastic calcium sparks. Biophys. J. 80:103-120.