Page 26 - YORAM RUDY BOOK FINAL

P. 26
onset (arrow in panel D), indicative of channel accumulation in the open state. The current does

not increase any further during the action potential. In contrast, there is very little instantaneous
I current (arrow in panel C), reflecting minimal channel accumulation in the open state between
Ks
beats. Instead, the current increases more rapidly than at slow rate, peaking at the end of the action

potential, where it is most effective in causing repolarization and action potential shortening.

In contrast to KCNQ1, I current is conserved during the early phase of the action potential
Ks
where it is least effective as a repolarizing current. This property, which allows I to peak during the
Ks
repolarization phase, results from channel accumulation in zone 1 of closed states between beats.

From zone 1, channels open quickly at fast rate to generate rapid increase of I current during the
Ks
action potential. Figure 2.11E compares I and KCNQ1 accumulation in zone 1 at fast (CL=250ms)
Ks
and slow (CL=1000ms) rates. There is large increase in zone 1 occupancy of I (by 0.25) as the rate in-
ks
creases. In contrast, KCNQ1 occupancy remains practically constant (increase is only 0.04). With this
mechanism, I ability to cause APD adaptation is far superior to that of KCNQ1, as evident from the
Ks
steeper adaptation curve with I in Figure 2.11F.
Ks

The ability of I to conserve current for the action potential repolarization phase is a result
Ks
of its enhanced capacity to build an available reserve (AR) of channels at fast rate. This property
results from the kinetic changes conferred on the channel by the modulatory effects of KCNE1.
Interestingly, as described in conjunction of Figure 2.8, I the second repolarizing current, also
Kr,
conserves current during the early phase of the action potential and peaks during the repolarization
phase. However, it does so via a very different mechanism; I channels inactivate very rapidly
Kr
following activation and then recover from inactivation during the action potential to generate
maximum open state occupancy and current during the repolarization phase.

The clinical implication of the available reserve property of I is demonstrated in the
Ks
simulation of Figure 2.12. In this study, I was blocked to simulate its reduction by mutations or by
Kr
drugs (various drugs, including certain antibiotics and antipsychotic agents, block I ). I reduction
Kr Kr
is a precursor to arrhythmia, especially after a pause. Shown in the figure are action potentials
computed with KCNQ1 (gray) or with I (black). The post-pause action potential with KCNQ1 shows
Ks
abnormal repolarization and an early after-depolarization (EAD) that can trigger arrhythmia. With
I , normal repolarization is restored. Thus, due to its kinetic properties I can provide “repolarization
Ks Ks
reserve” when I is compromised by disease or by drugs .
85
Kr
2.6. The Human Ventricular Myocyte 18

Cellular electrophysiology experiments are usually performed with channels expressed in
non-myocytes, or with nonhuman (rodent or other mammalian) myocytes. In previous sections
we presented and applied theoretical models of the guinea pig and canine ventricular AP. The
applicability of these models and experiments to human electrophysiology and Ca cycling is