Page 52 - Cardiac Electrophysiology | A Modeling and Imaging Approach

P. 52

Figure 2.32. Markovian models of wild-type (WT) and ∆KPQ mutant Na channels. The WT
+
channel (top, green) contains 3 closed states, an open state, and fast and slow inactivated states.
The ∆KPQ channel has two modes of gating: background (or dispersed) mode (blue) and a burst
mode (red) in which channels fail to inactivate. U and L prefixes to ∆KPQ states indicate upper
and lower mode. Adapted from Clancy and Rudy [125] with permission of Springer Nature.

recovery from inactivation observed experimentally. The burst mode does not contain an
inactivation state, representing the transient failure of inactivation of mutant channels.

A comparison of simulated and experimentally recorded wild-type single-channel traces

is provided in Figure 2.33A. In response to a depolarizing pulse channels open and inactivate,
showing only a single opening event on each tracing. Figure 2.33B shows simulated and recorded
traces of ΔKPQ mutant channel gating. In the background mode, secondary openings are
present. This is a result of the altered kinetic properties; faster opening increases the population

of channels in the fast-inactivated state (IF), and faster recovery from this state (IF to O) increases
the probability of channel re-openings. Most mutant channels (>90%) reside in the background
mode. However, there is a small probability of channels crossing into the burst mode where they
are “trapped” as a result of even smaller probability for returning to the background mode. In the

burst mode that lacks inactivation, channels fluctuate between closed and open state, displaying
frequent openings (“bursting”) in the recorded and simulated traces (bottom of Figure 2.33B).