Page 78 - YORAM RUDY BOOK FINAL

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Several other structural aspects that affect discontinuous conduction at the cellular scale

are briefly summarized below:

Cell Size. Conduction velocity and the degree of discontinuity depend not only on the magnitude

of intercellular coupling, but also on the dimensions of the cell (the path-length of relatively
low cytoplasmic resistivity between gap junctions). Simulated propagation in networks of adult
canine (large) ventricular cells and neonatal rat (small) heart cells demonstrated the importance
of cell size in determining cell-to-cell delay (and therefore, conduction velocity) and dV /dt
m max
during transverse propagation in the anisotropic cardiac tissue .
186

Localization of Sodium Channels at Gap Junctions. It is becoming increasingly evident that the
spatial organization of the cell plays a most important role in its function. For example, proximity

of L-type calcium channels that are clustered in the T-tubules to ryanodine receptors in junctional
sarcoplasmic reticulum is crucial to a normal calcium-induced-calcium-release process. In
general, cell signaling and regulation of various cell functions by regulatory pathways
(e.g. ß-adrenergic pathway, CaMKII pathway) depend on spatial proximity to target proteins.
In the context of action potential propagation in cardiac tissue, it was found that sodium channels

cluster near gap junctions 187,188 . For normal gap junction conductance, simulations demonstrated
that the effect of this co-localization is not significant. However, when gap junction coupling is
greatly reduced (<10% of normal) the clustering of sodium channels at the junctions can facilitate

conduction .
189

Reflection of Discontinuities of Conduction in Extracellular Electrograms. For excitation in a
continuous structure (e.g., the nerve axon), the extracellular potential recorded at a site near the
structure (the electrogram) is biphasic, displaying a positive then negative deflection (in time) as

the action potential passes under the extracellular electrode. The time of local activation is taken
as the point of steepest negative slope (“intrinsic deflection”) on the electrogram; it coincides with
dV /dt of the action potential . Figure 3.4 shows simulated electrograms for action
190
m max
potential propagation in a linear strand of cardiac cells (same model as in Figure. 3.1, bottom
panel) for two conditions: normal cell-to-cell coupling (panel A) and reduced coupling (panel B).
(The methodology of computing extracellular potentials is presented in Section 4 of this mono-
graph). During propagation in the well coupled fiber, the action potential upstroke (V ) and the
m
extracellular electrogram (ϕ ) are smooth and do not reflect the underlying discrete structure of
e
the multicellular fiber (Figure 3.4A). In contrast, at reduced gap junction coupling (Figure 3.4B)
irregularities are evident in both V and ϕ . In addition to the main negative deflection, which
m e
reflects activation of the local cell, there is an early positive hump (marked 1 in Figure 3.4B) which

reflects activation of the upstream neighboring cell and a late notch (marked 2 in Figure 3.4B)
which corresponds to activation of the downstream neighboring cell. These results demonstrate
that for normal coupling the cardiac electrogram is indistinguishable from an electrogram
generated by action potential propagation in a continuous electrical syncytium. However, when