CaM-binding domains in the C terminus and DIII--DIV linker region
control the effects of lidocaine on NaV1.5 steady-state
availability. A, voltage dependence of inactivation in cells
expressing WT, A1924T, or FIF/AAA (1.5 μg cDNA each) in low or high
[Ca2+]i. In high
[Ca2+]i, WT, A1924T, and FIF/AAA
V½ of inactivation were not significantly different
(-71.3 ± 0.9 mV (•; n = 24), -74.7 ± 1.9 mV
(▴; n = 13), and -73.7 ± 1.0 mV (▪; n =
13), respectively (p = NS)). In low
[Ca2+]i, the V½ of
inactivation of WT significantly differed from A1924T and FIF/AAA (-79.6
± 1.0 mV (○; n = 22), -87.4 ± 1.2 mV (▵;
n = 11; p < 0.05), and -85.9 ± 0.9 mV (□;
n = 9; p < 0.05), respectively). B,
V½ for A1924T in the absence or presence of lidocaine
in high [Ca2+]i was -74.7 ± 1.9 mV
(•; n = 13) and -75.4 ± 1.4 mV (○; n = 9),
respectively (p = NS). Left inset, voltage-dependent
inactivation for WT NaV1.5 under the same conditions. Right
inset, representative current traces in 1 μm
[Ca2+]i, in the presence (left) or
absence (right) of lidocaine. Black traces show currents
obtained at -20 mV after a prepulse at -160 mV, the small lines show
the currents obtained after a prepulse at -80 mV. Decay rates of the currents
at -20 mV after a prepulse to -160 mV were fit with the sum of two exponential
components. The biexponential decay rates of A1924T in high
[Ca2+]i in the absence (τf =
0.51 ± 0.02; τs = 2.46 ± 0.17) and presence of
lidocaine (τf = 0.57 ± 0.05; τs = 2.42
± 0.26) were not different (p = NS). C,
voltage-dependent inactivation of NaV1.5 FIF/AAA in the absence or
presence of lidocaine in high [Ca2+]i.
V½ was -73.7 ± 1.0 mV (•; n =
13) in the absence and -74.1 ± 0.6 mV (○; n = 5) in the
presence of lidocaine (p = NS). Left inset, same as in
B. Right inset, representative NaV1.5 FIF/AAA currents in
1 μm Cai, in the presence (left) or
absence (right) of lidocaine. Color coding is as described in
B. The biexponential decay rates of NaV1.5 FIF/AAA in high
[Ca2+]i in the absence (τf =
0.54 ± 0.03; τs = 2.7 ± 0.33), and presence of
lidocaine (τf = 0.52 ± 0.05; τs = 2.27
± 0.42) were not different (p = NS). D, shifts in the
V½ of steady-state inactivation of
NaV1.5 WT, A1924T, and FIF/AAA with or without 50, 300, or 2000
μm lidocaine in high [Ca2+]i from
B and C and Fig.
1A.