Biomedical Engineering Reference
In-Depth Information
trigger Ca
2+
through sarcolemmal LCCs. This failure is demonstrated in Figure
3E. The figure shows normalized peak Ca
2+
flux through RyR channels (ordi-
nate) as a function of membrane potential (mV; abscissa). Filled circles are ex-
perimental measurements from the work of Wier et al. (50), 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 the 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 the potential for which electrical
the 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 common pool model dynamics. LCCs not only un-
dergo voltage- but also Ca
2+
-dependent inactivation (51,52). Inactivation de-
pends on local subspace Ca
2+
concentration, and occurs as Ca
2+
binding to
calmodulin (52), 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. 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 (52,53) (see Figure 4C). This
implies in turn that there is a very strong coupling between Ca
2+
release from
JSR into the local subspace, and regulation of inactivation of the LCC. When
this newly revealed balance between voltage- and Ca
2+
-dependent inactivation is
incorporated into common pool models, the models become unstable, exhibiting
alternating short and long duration APs (31,54) (see Figure 4D). The reason for
this is intuitively clear—since JSR Ca
2+
release is all or none in these models,
Ca
2+
-dependent inactivation of LCCs is all-or-none, depending on whether re-
lease has or has not occurred. Since L-type Ca
2+
current is a major contributor to
inward current during the plateau phase of the AP, its biphasic inactivation leads
to instability of AP duration. This, unfortunately, constitutes a fatal weakness of
common pool models.
The fundamental failure of common pool models described above suggests
that more biophysically based models of excitation-contraction coupling must
be developed and investigated. Understanding of the mechanisms by which Ca
2+
influx via LCCs triggers Ca
2+
release from the JSR has advanced tremendously
with the development of experimental techniques for simultaneous measurement
of LCC currents and Ca
2+
transients and detection of local Ca
2+
transients, and
this has given rise to the local control hypothesis of EC coupling (19,50,55,56).
As illustrated schematically in Figure 4A, this hypothesis asserts that opening of
an
individual
LCC in the T-tubular membrane triggers Ca
2+
release from the
