Page 53 - Cardiac Electrophysiology | A Modeling and Imaging Approach

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Figure 2.33. Channel gating. A. WT single channel records from model simulation (left, green)
and experiment (right, black) showing only single opening events in response to depolarization.
B. ∆KPQ single channel records in the background mode (top 3 traces) and burst mode (bottom
2 traces). Note second openings in background mode and fluctuation between closed and open
states in burst mode, in absence of inactivation. Traces on left are simulated; traces on right are
experimentally recorded. Adapted from Clancy and Rudy [125] with permission of Springer Nature.
Experimental data from Chandra et. al. [126] with permission from the American Physiological
Society.

The reopening and bursting of ΔKPQ channels suggest that they generate a significant
late I current during an action potential plateau. This possibility and its effect on the action
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potential are examined in the simulations of Figure 2.34. The Markov models of Figure 2.32
were introduced into the LRd ventricular cell model, which was then paced at various rates.

In Figure 2.34, simulated action potentials (top) are shown with corresponding macroscopic I
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current (bottom) for: (I) wild-type paced at CL=400ms; (II) ΔKPQ mutant at CL=400ms; (III) ΔKPQ
at a slower rate of CL=600ms. In (IV), ΔKPQ experimental data are included for comparison ,
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showing close resemblance of the I trace to that simulated in (II).
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During a wild-type action potential, I has a large early spike that generates the action
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potential upstroke. This early peak decays very quickly, reflecting the single opening of each
individual ion channel. In contrast, secondary re-openings in background mode and bursting in

the burst mode of ΔKPQ channels generate a late component of macroscopic I current during
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the action potential plateau. This late current is only 1% of the early peak I . However, despite its
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small magnitude, it is sufficient to shift the delicate balance of currents in the inward direction,