Page 87 - YORAM RUDY BOOK FINAL

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potentials are shown in Figure 3.9B, with I Ca,L (solid line) or without I Ca,L (dashed line) included in

the computation. In the simulation, gap junction coupling was decreased 100-fold relative to
normal, a value slightly higher than the coupling at which conduction failure occurs in the
absence of I Ca,L . While the action potential upstrokes are identical with or without I Ca,L , indicat-
ing that it does not contribute directly to local excitation, the early plateau is significantly higher

when I Ca,L is present. The higher voltage increases the driving force for axial current to downstream
tissue, providing more depolarizing charge to the neighboring downstream cell. Similar to
Figure 3.6B, we compute and compare the depolarizing charge contribution from I Ca,L and I .
Na
In the simulation of Figure 3.9B (bar graph inset) Q :Q = 1.47, indicating similar charge
Na
Ca
contributions from the two currents. With further reduction of cell-to-cell coupling (Figure 3.9C)
Q :Q = 0.26 and I Ca,L contributes more depolarizing charge than I , becoming the major source
Na
Ca
Na
of charge for sustaining conduction. This property of highly discontinuous conduction is in sharp
contrast to slow conduction due to reduced membrane excitability (Figure 3.6) where I
Na
dominated conduction even when it was greatly suppressed, with only minor contribution from
I Ca,L . Note however, that even when Q >Q I is still needed to depolarize the membrane
Na Na
Ca
potential into the range of I Ca,L activation.

The switch from I to I Ca,L supported conduction occurs when there are long inter-
Na
cellular conduction delays. A downstream sink cell is activated when its upstream source
neighbor is already well into the plateau phase of its action potential. During the plateau, I is
Na
already inactivated and I Ca,L is the major source of depolarizing charge. Because Q and Q are
Ca
Na
obtained from integrating the currents over this long delay, Q becomes comparable or even
Ca
greater than Q , despite the much larger I magnitude during the short duration of the action
Na
Na
potential upstroke.

The switch of the ionic mechanism that supports conduction in the presence of long
conduction delays is an excellent example of the close interaction between the “passive” tissue
structure (sink, or load) and the “active” membrane ionic currents (source) during conduction.
Alteration of tissue properties (e.g. gap junction conductance in the example above) can alter the

role of ion-channel currents even in the absence of changes to intrinsic channel properties (e.g. its
gating kinetics or density of expression in the membrane). This functional modulation of
membrane currents by the tissue is a feedback mechanism from the load (sink) to the source
that is necessary for maintaining function when structural changes occur. It expands the concept

that the source is determined only by its intrinsic properties to include the intimate bi-directional
interplay between soure and sink during action potential propagation.

The influence of I Ca,L on conduction over a range of gap junction coupling is shown in

Figure 3.9D. SF with (solid line) or without (dashed line) I Ca,L is biphasic, displaying an increase to a
maximum as coupling is reduced, followed by a fast decline toward conduction failure (similar to
Figure 3.8). However, at reduced coupling SF with I Ca,L becomes significantly larger and
conduction is maintained at lower levels of gap junction coupling.