Page 48 - YORAM RUDY BOOK FINAL

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Figure 2.28. A. Three simulated single-channel current traces for a step depolarization V from
m
-80 to 60 mV. B. The ensemble current (average of 100 traces) fits the experimental data 123a . C. An
expanded section of a simulated single-channel trace. Experimentally identified current levels 123a
(dashed lines, black entries) and SC computed from simulations (blue entries) are shown. D. A
current amplitude histogram of simulated single-channel traces at 60 mV (blue) and the
corresponding experimental data (shaded gray) 123a . The arrow indicates the mean current amplitude
histogram (0.47 pA, also indicated by the arrow in E). E. Similar histograms (to D) are constructed for
a range of V to obtain the microscopic I – V relationship (blue line) that fits experimental data
m
(symbols) with a slope (mean conductance) of 3.27 pS (as determined experimentally 123a ). From
Ramasubramanian and Rudy [120]. Reproduced with permission from Elsevier.

The following mechanistic insights were obtained from the simulations: 1. KCNE1, through
electrostatic interactions with KCNQ1, increased the probability of “visiting” conducting pore
conformations on activation trajectories, thereby increasing I current compared to KCNQ1.
Ks
2. KCNE1 slowed I activation compared to KCNQ1 by impeding the voltage-sensor movement
Ks
and reducing its coupling to pore opening. 3. The S4S5L plays an important role in the modulatory
effects by KCNE1 during activation. An initial relative movement between S4 and S4S5L is possible
by the dihedral angles of Gly245 – Gly246, which can undergo significant changes due to their

small side chains. This enables an initial fast response of S4 to membrane depolarization. It then
constraints the additional translation of S4 by coupling it to the swinging movement of S4S5L
about the N-terminus of S5. This mechanism contributes to the two movements of the voltage
sensor, described in the previous section. KCNE1 slows the S4S5L movement and the slow
component of S4 movement through electrostatic interactions. 4. Cooperativity between voltage

sensors is not required for pore opening in either KCNQ1 or I . Not all voltage sensors need to be
Ks
in the activated (up) position for the channel to be in a conducting state, as the conformational
space contains open-pore conformations with one or more voltage sensors in low Z positions.