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corresponding S2 interval. The mechanism can be understood by
contrasting the magnitude of Ca
2+
release events for S2 responses
a
and
b
in figure 9.5a. Since the S2 interval is long for response
b
,
this provides ample time for SR Ca
2+
levels to be restored by the SR
Ca
2+
-ATPase, and Ca
2+
release amplitude is large. This large release
event depletes SR Ca
2+
levels substantially so that the release event
b
'
initiated 3 s later by the S3 stimulus is small. The converse is true for
release events
a
and
a
'.
The responses shown in figures 9.5a-b agree very well with experi-
mental data (contrast these model data with experimental findings
in Wier et al., fig. 3 [34]), and show that common pool models are capa-
ble of describing complex intracellular Ca
2+
cycling processes
determined by the rate of SR Ca
2+
loading by the SR Ca
2+
-ATPase.
However, common pool models, as noted previously, are not able to
reproduce a very fundamental behavior of cardiac myocytes—SR
Ca
2+
release, which is a smooth and continuously graded function of
trigger Ca
2+
through sarcolemmal LCCs. This failure is demonstrated
in figure 9.5c. This figure shows normalized peak Ca
2+
flux through
RyR channels (ordinate) as a function of membrane potential (mV,
abscissa). Closed circles are experimental measurements from the
work of Wier et al. [35], showing that release flux increases smoothly
to a maximum flux at about 0 mV, and then decreases to near zero at
more depolarized potentials. Release flux increases from
40 to 0 mV,
since over this potential range the open probability of LCCs increases
very steeply, reaching a maximum value. Release flux decreases over
the potential range greater than 0 mV because electrical driving force
on Ca
2+
decreases monotonically. The solid line shows release flux
for the Jafri-Rice-Winslow guinea pig ventricular myocyte model.
Release is all-or-none, with regenerative release initiated at a membrane
potential causing opening of a sufficient number of LCCs (~
−
15 mV),
and release terminating at a potential for which electrical driving force
is reduced to a critical level (~
−
40 mV).
This all-or-none behavior of Ca
2+
release in common pool models
has very important implications for the integrative function of the
cell. As noted previously, LCCs not only undergo voltage- but also
Ca
2+
-dependent inactivation [36,37]. Inactivation depends on local sub-
space Ca
2+
concentration, and occurs as Ca
2+
binding to calmodulin [37],
which is tethered to the LCC, induces the channel to switch from a
normal mode of gating to a mode in which transitions to open states
are extremely rare or nonexistent (these Ca
2+
-inactivated states were
labeled “Mode Ca” in the model of figure 9.3). Recent experimental
data have demonstrated that voltage-dependent inactivation of LCCs
is a slow and weak process, whereas Ca
2+
-dependent inactivation is
relatively fast and strong [37,38]. This in turn implies that there is a
very strong coupling between Ca
2+
+
release from JSR into the local
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