Saleet Jafri
Associate Professor
School of Computational Sciences
George Mason University
 
Calcium sparks are the elementary Ca release events that underlie
the coupling of electrical excitation and contraction in heart and
skeletal muscle and play an important role in regulating tone in smooth
muscle. The properties and significance of Ca sparks have been studied
in detail, yet the mechanism for Ca spark termination remains unclear.
A mathematical model based on recent experimental data was developed to
study the mechanism of calcium spark generation and termination in
heart.
 
Ryanodine receptors (RyRs) are Ca channels in the sarcoplasmic
reticulum (SR) that control Ca release from the SR and are thus
responsible for Ca sparks. RyRs are activated by Ca itself and, in
heart muscle, are triggered to release calcium by the influx of Ca
through voltage-gated L-type Ca channels (dihydropyridine receptors,
DHPRs) that are located close to the RyRs. The DHPRs are found in the
sarcolemma and transverse tubular (T-tubule) membrane. The DHPRs are
very close to RyRs, sharing a common very narrow "subspace" that exists
between the T-tubular membrane and the SR (~15 nm wide). Three recent
results are important for the proposed model. First, it was discovered
that RyRs in heart are packed into arrays of up to hundreds of RyRs.
Second, a physical coupling among adjacent RyRs has been shown to
affect gating of RyRs. Third, the open probability of the RyRs has
been shown to decline with lower SR Ca content.
 
The model includes an array of RyRs (up to 100) that share a
subspace with one DHPR. Each RyR is modeled as an independent two-
state channel that is activated by subspace calcium. The RyR open
probability (Po) is influenced by the SR lumenal [Ca], with the Po
decreasing as SR lumenal [Ca] declines. Additionally, the state of one
RyR influences the state of other RyRs through a co-operativity
factor. This last feature is used to simulate "coupled gating" of RyRs.
 
Our model of Ca sparks nicely reproduces many features of Ca
sparks that have been observed experimentally in heart. Ca sparks are
activated at a very low rate under resting conditions but Ca sparks
are "triggered" when there is an influx of Ca into the subspace, as
occurs when DHPRs are activated. Ca spark durations, amplitudes, and
profiles are similar to experiment. When the RyR dependence on SR
lumenal Ca is removed, Ca sparks fail to terminate. Ca spark durations
also increase when the coupling is reduced; this mimics the effect of
agents such as FK506 that disrupt coupled gating. The remarkable
success of this "sticky cluster" model of the cardiac Ca spark,
suggests that the two central novel features of our model (coupled
gating of RyRs and the dependence of RyR Po on SR lumenal [Ca]) may
play an important role in regulating SR Ca release in heart.