OF WORK During the previous project period we have concentrated on the mechanisms involved in termination of local calcium release events. In collaboration with Eduardo Rios, we devised calcium spark simulations that were compared with high-resolution spark images obtained from mammalian skeletal muscle. This analysis showed that spark calcium sources are spatially extended and involve coordiated opening of large numbers of calcium release channels (ryanodine receptors, RyRs). We developed spark simulation algorithms in the FACSIMILE language which can be fitted to experimental records by non-linear least-squares methods. These simulations now take into account the possibility of local depletion of SR lumenal calcium, which has been suggested as a spark-termination mechanism. Our Monte Carlo simulations of local SR calcium release showed that the quantal decomposition of calcium sparks found by Dr. Cheng's group could be explained by very strong inactivation of of resting RyRs by local cytosolic calcium. However, to date, the existence of such a phenomenon is not confirmed by studies on isolated RyRs. We are therefore modifying the simulation algorithm to take into account dynamic local depletion of calcium in individual SR release terminals and regulation of RyR gating by lumenal Ca2+. This involves major alteration of the algorithm to make SR calcium a local dynamical variable. We will then determine whether the quantal statistics found experimentally can be accounted for by the lumenal calcium regulation mechanism. In other studies, we have modeled the effect of local spontaneous calcium release events on currents in pacemaker cells. The modeling shows that diastolic calcium release couples strongly via sodium-calcium exchange current so that SR calcium oscillations become a dominant mechanism in regulating heart rate. This is consistent with recent experimental results from our laboratory. We have also analyzed the first single-channel L-type calcium currents recored under physiological conditions and find that the mechanism of calcium-inactivation of the channel appears to be consistent with the mode-shift mechanism hypothesized in our stochastic simulations of excitation-contraction coupling.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000844-07
Application #
6815419
Study Section
(LCS)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2003
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Tetievsky, Anna; Cohen, Omer; Eli-Berchoer, Luba et al. (2008) Physiological and molecular evidence of heat acclimation memory: a lesson from thermal responses and ischemic cross-tolerance in the heart. Physiol Genomics 34:78-87
Cohen, Omer; Kanana, Hifa; Zoizner, Ronen et al. (2007) Altered Ca2+ handling and myofilament desensitization underlie cardiomyocyte performance in normothermic and hyperthermic heat-acclimated rat hearts. J Appl Physiol 103:266-75
Vinogradova, Tatiana M; Lyashkov, Alexey E; Zhu, Weizhong et al. (2006) High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells. Circ Res 98:505-14
Bogdanov, Konstantin Y; Maltsev, Victor A; Vinogradova, Tatiana M et al. (2006) Membrane potential fluctuations resulting from submembrane Ca2+ releases in rabbit sinoatrial nodal cells impart an exponential phase to the late diastolic depolarization that controls their chronotropic state. Circ Res 99:979-87
Stern, Michael D (2006) How to give a cell a heart attack. Circ Res 99:111-2
Maltsev, Victor A; Vinogradova, Tatiana M; Bogdanov, Konstantin Y et al. (2004) Diastolic calcium release controls the beating rate of rabbit sinoatrial node cells: numerical modeling of the coupling process. Biophys J 86:2596-605
Vinogradova, Tatiana M; Zhou, Ying-Ying; Maltsev, Victor et al. (2004) Rhythmic ryanodine receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ Res 94:802-9
Csernoch, L; Zhou, J; Stern, M D et al. (2004) The elementary events of Ca2+ release elicited by membrane depolarization in mammalian muscle. J Physiol 557:43-58
Stern, Michael D; Cheng, Heping (2004) Putting out the fire: what terminates calcium-induced calcium release in cardiac muscle? Cell Calcium 35:591-601
Wang, Shi Qiang; Stern, Michael D; Rios, Eduardo et al. (2004) The quantal nature of Ca2+ sparks and in situ operation of the ryanodine receptor array in cardiac cells. Proc Natl Acad Sci U S A 101:3979-84

Showing the most recent 10 out of 21 publications