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Results: 6

1.
Figure 6

Figure 6. Conductance of simulated sodium channels underlying membrane voltage simulations in Fig. 5F. From: A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita.

All parameters are identical to those used for Fig. 5F, except sodium conductance, rather than membrane voltage, is shown for the simulated WT and mutant channels.

David E Featherstone, et al. J Physiol. 1998 February 1;506(Pt 3):627-638.
2.
Figure 2

Figure 2. Voltage dependence of activation and fast inactivation. From: A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita.

A shows the voltage dependence of activation for WT, R1441P and R1441C, as measured by the fraction of channels that open in response to a test pulse from -180 mV. A Boltzmann distribution has been fitted to each set of data, to yield the following fit coefficients: WT: V½= -39 mV, z= 3.54; R1441C: V½= -41 mV, z= 3.19; R1441P: V½= -40 mV, z= 2.91. B shows the voltage dependence of steady-state fast inactivation, as measured by the fraction of activatable (not inactivated) channels at 0 mV following a 500 ms prepulse to various potentials (see protocol diagram, top right). A Boltzmann distribution was fitted to each set of data, to yield the following coefficients: WT: V½= -96 mV, z= 3.43; R1441C: V½= -108 mV, z= 1.76; R1441P: V½= -111 mV, z= 1.71.

David E Featherstone, et al. J Physiol. 1998 February 1;506(Pt 3):627-638.
3.
Figure 3

Figure 3. Tail current decay rates. From: A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita.

A-D shows typical tail currents during a step to voltages from -120 to +20 mV, following a brief (0.5 ms), channel-opening pulse to +50 mV (see protocol diagram in E), for WT (A), R1441C (B), R1441P (C) and IFM1303QQQ (D). Single exponentials were fitted to tail current decays to derive the mean ±s.e.m. time constants plotted in E (filled symbols and lines, left vertical axis). The fraction of tail current that decayed (due to deactivation) in the fast inactivation-removed mutant IFM1303QQQ is also plotted in E (open circles, right vertical axis), and was fitted by a Boltzmann distribution (dashed line) with the following coefficients: V½= -41 mV, z= 4.3.

David E Featherstone, et al. J Physiol. 1998 February 1;506(Pt 3):627-638.
4.
Figure 5

Figure 5. Simulations of paramyotonia congenita. From: A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita.

A, a simulated membrane response (a single action potential) to a 0.5 ms 200 μA cm−2 stimulus, at 37 °C. B, the simulation was run under identical conditions except that a simulated temperature of 27 °C was used. In C and D, the simulation was repeated, except in this case fast inactivation recovery was accelerated twofold and fast inactivation onset slowed fourfold in 50 % of sodium channels in order to mimic previously reported defects in paramyotonia congenita. As in A and B, temperatures of 37 °C (C) and 27 °C (D) were simulated. In E and F, slowed deactivation has been added to the mutant fast inactivation simulated in C and D, in order to mimic the complete suite of defects we observed in this study.

David E Featherstone, et al. J Physiol. 1998 February 1;506(Pt 3):627-638.
5.
Figure 4

Figure 4. Sodium currents in response to action potential command waveforms. From: A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita.

A, an action potential-shaped command potential was used to elicit sodium currents. B, the downstroke of the action potential command was eliminated. C, the action potential rise was replaced by a rectangular pulse to open channels, followed by an action potential ‘downstroke’. A membrane voltage recording (reflecting the actual clamped voltage in the macropatch) is shown in the top panels of A-C. Typical WT, R1441C and R1441P sodium currents evoked by these protocols are shown below each voltage trace. A holding potential of -90 mV was used in order to mimic muscle fibre rest potential. Action potential waveforms (see Methods) were based on recordings from rat skeletal muscle shown in Cannon et al. (1993). No leak subtraction was used for any of the recordings shown, but seal resistances were 50-100 GΩ and sodium currents were large (several hundred picoamps). Dashed lines have been added to help compare timing of voltage and current recordings. Peak amplitude was normalized in each panel. Currents were normalized to size of the first peak in A, and second peak in C.

David E Featherstone, et al. J Physiol. 1998 February 1;506(Pt 3):627-638.
6.
Figure 1

Figure 1. Rates of fast inactivation. From: A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita.

A-C shows typical macropatch sodium currents evoked by test pulses from -180 mV to various potentials, for WT (A), R1441C (B), and R1441P (C) sodium channels, consisting of both α and β1 subunits. Reversal potential was between +50 and +60 mV. Single exponentials were fitted to test pulse decay to derive the mean ±s.e.m. time constants for fast inactivation shown in D. D shows that fast inactivation in WT is faster than in both R1441P and R1441C, from -40 to +40 mV. However, inactivation time constants for R1441P and R1441C are not significantly different. In E, mean ±s.e.m. time constants for inactivation at -80 to -50 mV are plotted (filled symbols). These values were derived by fitting a single exponential to a plot of 0 mV test pulse amplitude vs. prepulse duration (see upper protocol diagram in E). E also shows mean ±s.e.m. time constants for fast inactivation recovery (open symbols). Recovery time constants were measured by fitting a single exponential to a plot of 0 mV test pulse amplitude vs. interpulse duration, where the interpulse followed a 500 ms step to 0 mV which fully inactivated all channels (see lower protocol diagram in E).

David E Featherstone, et al. J Physiol. 1998 February 1;506(Pt 3):627-638.

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