Table 1 Open in new tab Biophysical...

Variant

I_Na density at −10 mV (pA/pF)

V_0.5,act (mV)

V_0.5,inact (mV)

I_Na-P at −10 mV (% of peak)

t recovery (ms)

458.3 ± 55

−17.56 ± 0.42

−51.70 ± 0.96

1.06 ± 0.29

1.19 ± 0.03

P-value

–

N1662D

95.2 ± 17****

−17.24 ± 0.44^NS

−39.56 ± 1.3****

0.54 ± 0.02****

–

P-value

<0.0001

0.999

<0.0001

–

<0.0001

Q1494A

212.7 ± 28**

−13.39 ± 0.47****

−36.75 ± 2.1****

0.51 ± 0.04****

–

P-value

0.048

<0.0001

–

<0.0001

Q1494E

195.8 ± 54**

−16.01 ± 0.72^NS

−36.15 ± 1.3****

0.61 ± 0.04****

–

P-value

0.002

0.463

<0.0001

–

<0.0001

Q1494L

103.0 ± 14****

−15.28 ± 0.74*

−43.02 ± 1.4****

0.69 ± 0.03****

–

P-value

<0.0001

0.044

<0.0001

−

<0.0001

Q1494K

38.3 ± 7.9****

−9.03 ± 0.58****

−43.22 ± 0.46****

1.01 ± 0.08**

–

P-value

<0.0001

–

0.0038

F1651C

461.5 ± 60^NS

−16.12 ± 0.59^NS

−38.92 ± 0.53****

4.86 ± 0.57****

0.67 ± 0.02****

P-value

>0.999

0.482

<0.0001

M1501V

265.4 ± 51*

−10.81 ± 0.61****

−42.63 ± 0.68****

4.04 ± 0.79**

0.84 ± 0.04****

P-value

0.032

<0.0001

0.0001

0.0028

<0.0001

M1501T

275.2 ± 27^NS

−18.18 ± 0.58^NS

−46.37 ± 0.54^NS

3.63 ± 0.96*

0.69 ± 0.01****

P-value

0.076

0.996

0.007

0.021

<0.0001

L1657P

109.8 ± 24****

−16.51 ± 0.84^NS

−44.82 ± 3.7**

0.62 ± 0.03****

–

P-value

<0.0001

0.844

0.0036

–

<0.0001

P1658S

140.6 ± 22***

−14.34 ± 0.57***

−42.62 ± 0.68****

5.91 ± 0.99****

0.59 ± 0.02****

P-value

<0.0001

0.0002

<0.0001

A1659V

361.3 ± 50^NS

−17.00 ± 0.63^NS

−46.66 ± 0.60*

5.64 ± 0.43****

0.77 ± 0.05****

P-value

0.562

0.992

0.026

<0.0001

Table 1

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Biophysical characteristics of the engineered and pathogenic Na_v1.2 variants relative to wild-type

Variant	I_Na density at −10 mV (pA/pF)	V_0.5,act (mV)	V_0.5,inact (mV)	I_Na-P at −10 mV (% of peak)	t recovery (ms)
WT	458.3 ± 55	−17.56 ± 0.42	−51.70 ± 0.96	1.06 ± 0.29	1.19 ± 0.03
n	22	22	22	22	18
P-value	–	–	–	–	–
N1662D	95.2 ± 17****	−17.24 ± 0.44^NS	−39.56 ± 1.3****	ND	0.54 ± 0.02****
n	16	16	16	–	14
P-value	<0.0001	0.999	<0.0001	–	<0.0001
Q1494A	212.7 ± 28**	−13.39 ± 0.47****	−36.75 ± 2.1****	ND	0.51 ± 0.04****
n	6	6	6	–	5
P-value	0.048	<0.0001	<0.0001	–	<0.0001
Q1494E	195.8 ± 54**	−16.01 ± 0.72^NS	−36.15 ± 1.3****	ND	0.61 ± 0.04****
n	6	6	6	–	6
P-value	0.002	0.463	<0.0001	–	<0.0001
Q1494L	103.0 ± 14****	−15.28 ± 0.74*	−43.02 ± 1.4****	ND	0.69 ± 0.03****
n	7	7	7	–	7
P-value	<0.0001	0.044	<0.0001	−	<0.0001
Q1494K	38.3 ± 7.9****	−9.03 ± 0.58****	−43.22 ± 0.46****	ND	1.01 ± 0.08**
n	9	9	8	–	8
P-value	<0.0001	<0.0001	<0.0001	–	0.0038
F1651C	461.5 ± 60^NS	−16.12 ± 0.59^NS	−38.92 ± 0.53****	4.86 ± 0.57****	0.67 ± 0.02****
n	7	7	7	7	6
P-value	>0.999	0.482	<0.0001	<0.0001	<0.0001
M1501V	265.4 ± 51*	−10.81 ± 0.61****	−42.63 ± 0.68****	4.04 ± 0.79**	0.84 ± 0.04****
n	7	7	6	7	7
P-value	0.032	<0.0001	0.0001	0.0028	<0.0001
M1501T	275.2 ± 27^NS	−18.18 ± 0.58^NS	−46.37 ± 0.54^NS	3.63 ± 0.96*	0.69 ± 0.01****
n	6	6	6	6	6
P-value	0.076	0.996	0.007	0.021	<0.0001
L1657P	109.8 ± 24****	−16.51 ± 0.84^NS	−44.82 ± 3.7**	ND	0.62 ± 0.03****
n	7	7	7	–	6
P-value	<0.0001	0.844	0.0036	–	<0.0001
P1658S	140.6 ± 22***	−14.34 ± 0.57***	−42.62 ± 0.68****	5.91 ± 0.99****	0.59 ± 0.02****
n	9	9	9	9	7
P-value	<0.0001	0.0002	<0.0001	<0.0001	<0.0001
A1659V	361.3 ± 50^NS	−17.00 ± 0.63^NS	−46.66 ± 0.60*	5.64 ± 0.43****	0.77 ± 0.05****
n	10	10	10	10	9
P-value	0.562	0.992	0.026	<0.0001	<0.0001

Variant	I_Na density at −10 mV (pA/pF)	V_0.5,act (mV)	V_0.5,inact (mV)	I_Na-P at −10 mV (% of peak)	t recovery (ms)
WT	458.3 ± 55	−17.56 ± 0.42	−51.70 ± 0.96	1.06 ± 0.29	1.19 ± 0.03
n	22	22	22	22	18
P-value	–	–	–	–	–
N1662D	95.2 ± 17****	−17.24 ± 0.44^NS	−39.56 ± 1.3****	ND	0.54 ± 0.02****
n	16	16	16	–	14
P-value	<0.0001	0.999	<0.0001	–	<0.0001
Q1494A	212.7 ± 28**	−13.39 ± 0.47****	−36.75 ± 2.1****	ND	0.51 ± 0.04****
n	6	6	6	–	5
P-value	0.048	<0.0001	<0.0001	–	<0.0001
Q1494E	195.8 ± 54**	−16.01 ± 0.72^NS	−36.15 ± 1.3****	ND	0.61 ± 0.04****
n	6	6	6	–	6
P-value	0.002	0.463	<0.0001	–	<0.0001
Q1494L	103.0 ± 14****	−15.28 ± 0.74*	−43.02 ± 1.4****	ND	0.69 ± 0.03****
n	7	7	7	–	7
P-value	<0.0001	0.044	<0.0001	−	<0.0001
Q1494K	38.3 ± 7.9****	−9.03 ± 0.58****	−43.22 ± 0.46****	ND	1.01 ± 0.08**
n	9	9	8	–	8
P-value	<0.0001	<0.0001	<0.0001	–	0.0038
F1651C	461.5 ± 60^NS	−16.12 ± 0.59^NS	−38.92 ± 0.53****	4.86 ± 0.57****	0.67 ± 0.02****
n	7	7	7	7	6
P-value	>0.999	0.482	<0.0001	<0.0001	<0.0001
M1501V	265.4 ± 51*	−10.81 ± 0.61****	−42.63 ± 0.68****	4.04 ± 0.79**	0.84 ± 0.04****
n	7	7	6	7	7
P-value	0.032	<0.0001	0.0001	0.0028	<0.0001
M1501T	275.2 ± 27^NS	−18.18 ± 0.58^NS	−46.37 ± 0.54^NS	3.63 ± 0.96*	0.69 ± 0.01****
n	6	6	6	6	6
P-value	0.076	0.996	0.007	0.021	<0.0001
L1657P	109.8 ± 24****	−16.51 ± 0.84^NS	−44.82 ± 3.7**	ND	0.62 ± 0.03****
n	7	7	7	–	6
P-value	<0.0001	0.844	0.0036	–	<0.0001
P1658S	140.6 ± 22***	−14.34 ± 0.57***	−42.62 ± 0.68****	5.91 ± 0.99****	0.59 ± 0.02****
n	9	9	9	9	7
P-value	<0.0001	0.0002	<0.0001	<0.0001	<0.0001
A1659V	361.3 ± 50^NS	−17.00 ± 0.63^NS	−46.66 ± 0.60*	5.64 ± 0.43****	0.77 ± 0.05****
n	10	10	10	10	9
P-value	0.562	0.992	0.026	<0.0001	<0.0001

Data are presented as mean ± standard error of the mean. The statistically significant differences between wild-type (WT) and mutant Na_v1.2 channels were determined using one-way ANOVA, followed by Dunnett’s post hoc test (*P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001). ND = not determined; NS = statistically not significant difference compared to WT. I_Na = sodium current; I_Na-P = persistent sodium current; n = number of independent experiments; t recovery = time constant of recovery from fast inactivation; V_{0.5 =act} = membrane potential for half-maximal activation; V_{0.5 =inact} = membrane potential for half-maximal inactivation.

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