Abstract
The majority of contractile calcium in cardiac muscle is released
from stores in the sarcoplasmic reticulum (SR), by a process of calcium-induced
calcium release (CICR) through ryanodine receptors. Because CICR
is intrinsically self-reinforcing, the stability of and graded regulation
of cardiac EC coupling appear paradoxical. It is now well established
that this gradation results from the stochastic recruitment of varying
numbers of elementary local release events, which may themselves
be regenerative, and which can be directly observed as calcium sparks.
Ryanodine receptors (RyRs) are clustered in dense lattices, and most
calcium sparks are now believed to involve activation of multiple
RyRs. This implies that local CICR is regenerative, requiring a mechanism
to terminate it. It was initially assumed that this mechanism was
inactivation of the RyR, but during the decade since the discovery
of sparks, no sufficiently strong inactivation mechanism has been
demonstrated in vitro and all empirically determined gating schemes
for the RyR give unstable EC coupling in Monte Carlo simulations.
We consider here possible release termination mechanisms. Stochastic
attrition is the spontaneous decay of active clusters due to random
channel closure; calculations show that it is much too slow unless
assisted by another process. Calcium-dependent RyR inactivation involving
third-party proteins remains a viable but speculative mechanism;
current candidates include calmodulin and sorcin. Local depletion
of SR release terminal calcium could terminate release, however calculations
and measurements leave it uncertain whether a sufficient diffusion
resistance exists within the SR to sustain such depletion. Depletion
could be assisted by dependence of RyR activity on SR lumenal Ca$^2+$.
There is substantial evidence for such lumenal activation, but it
is not clear if it is a strong enough effect to account for the robust
termination of sparks. The existence of direct interactions among
clustered RyRs might account for the discrepancy between the inactivation
properties of isolated RyRs and intact clusters. Such coupled gating
remains controversial. Determining the mechanism of release termination
is the outstanding unsolved problem of cardiac EC coupling, and will
probably require extensive genetic manipulation of the EC coupling
apparatus in its native environment to unravel the solution.
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