Page 24 - YORAM RUDY BOOK FINAL

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Figure 2.10. Kinetic transitions of I channels during the AP at slow and fast rate. A. Markovian
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model of the I channel . States are color coded: light green – zone 2 of closed states (C) for
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which not all voltage sensors have completed the first transition; blue – zone 1 of closed states for
which all four voltage sensors have completed the first (slow) transition before channel opening;
red – open states. B. I , V and channel state occupancies during the AP at slow pacing rate. I
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m
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increases slowly, generating maximum current at the end of the AP. Only 40% of channels reside
in zone 1 at AP onset. C. Same as B, but at fast pacing rate. There is accumulation of channels in
zone 1 (75% of channels at AP onset) from which they can open rapidly. As a result, open state
occupancy and I increase faster (steeper slope) than at slow rate, generating a large peak late
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during the AP when I can most effectively contribute to repolarization and APD shortening.
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Reproduced from Rudy and Silva [10], with permission of Cambridge University Press.
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approach that employs smaller Markov models of the four channel subunits was proposed ).
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Closed states in the model are divided into two zones: zone 2 (green) of channels with at least one
voltage sensor that has to make a first (slow) transition to the intermediate state, and zone 1 (blue)
of channels with voltage sensors that only need to make the (fast) second transition from the

intermediate to the activated state. As shown in Figure 2.10B, at slow rate (CL=1000ms) 60% of
channels reside in zone 2 before action potential depolarization and must make a slow transition to
zone 1 before opening; only 40% of the channels reside in zone 1, from where they can open rapidly.
In contrast, at fast rate (CL=300ms) channels do not have sufficient time between beats to make
the slow transition from zone 1 to zone 2 and they are “trapped” in zone 1. Nearly 75% of channels

accumulate in zone 1 before the action potential onset, leading to fast activation and rapid increase
of I current during the action potential. Note that there is very little accumulation of channels in
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the open state, rather, channels accumulate in zone 1 of closed states that are kinetically near the

open state. We termed these an “available reserve” (AR) of channels that can open quickly “on
demand” to cause fast increase of I towards the repolarization phase of the action potential, when
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it can effectively shorten APD. This novel mechanism of adaptation, which does not