Page 22 - YORAM RUDY BOOK FINAL

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the open state because of rapid inactivation and large occupancy of the inactivated state (Figure

2.8 B, C; purple trace). During most of the action potential, the balance between activation and
inactivation favors inactivation. As V repolarizes, channels begin to recover from inactivation and
m
open state occupancy reaches a maximum at a late phase of the action potential (Figure 2.8 B,

C; red trace). This generates a late peak of I current, at a time during the action potential when it
Kr
can have maximum effect on repolarization and APD. Note that peak I is similar at slow and fast
Kr
rates, a property that results from the much stronger voltage dependence than time dependence
of recovery from inactivation. This implies that in guinea pig ventricular myocytes I does not play
Kr
a primary role in rate-dependent adaptation of APD. In large mammals, including the human, I
Kr
is an important determinant of ventricular repolarization and its rate dependence.

The slow delayed rectifier, I , dominates rate-dependent repolarization in the guinea pig .
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Ks
In this species, I is large and slow to deactivate (I channels do not inactivate; following
Ks Ks
activation channels close by returning to closed states, a process termed deactivation). As a
consequence of slow deactivation, at fast rate not all channels close between beats and there is
channel accumulation in the open state, which acts to increase the current and shorten APD. In
large mammals and the human, I is smaller and its deactivation is faster, which brings to question
Ks
its participation in rate dependent repolarization. Yet, mutations in I are linked to hereditary
Ks
human arrhythmias associated with action potential prolongation and the long QT syndrome
(LQT1 and LQT5 ) that express clinically at high levels of ß-adrenergic tone (exercise or emotional
73
74
stress).

I is composed of four KCNQ1 α-subunits and a modulatory ß-subunit KCNE1. There is
9
Ks
evidence that the naturally assembled I channel contains four KCNQ1 and two KCNE1
Ks
subunits. KCNE1 acts to increase single channel conductance and expression of I relative to
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Ks
KCNQ1 alone 76,77,78 (four KCNQ1 subunits form a functioning homomeric channel in the absence of
KCNE1). KCNE1 also acts to slow channel activation, creating a significant delay before activation.
It also removes channel inactivation , which is present in KCNQ1 homomeric channels but not in
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I . To account for the activation delay, it was proposed that each of the four voltage sensors (S4
Ks
of each of the four KCNQ1 subunits) goes through two conformational transitions before channel
opening. Experimental evidence from Shaker potassium channels shows that arginine residues
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on S4 interact with acidic residues on S2 sequentially, providing a molecular mechanism for the
two-stage voltage sensor activation. This is depicted in Figure 2.9A, B, showing two closed
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conformations of the voltage sensors: resting (R ) and intermediate (R ). Once all four voltage
1 2
sensors are in the activated (A) state, the channel can open. The transition to the open state is
cooperative and voltage independent. 82

Figure 2.9C shows all possible combinations of the four voltage-sensor positions before
channel opening. There are 15 possible combinations, represented by 15 closed states (C – C ). In
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1 15
C , all four voltage sensors are in the R resting state (blue); in C one moved to the R state (red);
1 1 2 2