TY - JOUR
T1 - The inhibitory actions by lacosamide, a functionalized amino acid, on voltage-gated Na+ currents
AU - Huang, C. W.
AU - Hung, T. Y.
AU - Wu, S. N.
N1 - Publisher Copyright:
© 2014 IBRO.
PY - 2015/2/6
Y1 - 2015/2/6
N2 - The effect of lacosamide (LCS), a functionalized molecule with anti-convulsant properties, on ion channels was investigated, with the aid of patch clamp technology and simulation modeling. In NSC-34 neuronal cells, LCS was found to block voltage-gated Na+ current (INa) in a frequency- and concentration-dependent manner. With the two-step voltage protocol, a minimal change in the steady-state inactivation of INa was found in the presence of LCS. However, with repetitive stimulation, the pulse-to-pulse reduction in peak current was shown to be exponential, with a rate linearly related to both the inter-stimulus interval and the LCS concentration. In addition, the frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of NaV channels harboring either an accessible or an inaccessible binding site. LCS also increased the dimension of inactivation space of NaV-channel states, thereby producing the adaptive response of neurons to previous firing. LCS (30μM) had no effects on the non-inactivating component of INa, while it slightly decreased the amplitude of delayed-rectifier K+ current. Moreover, LCS suppressed the peak amplitude of INa in embryonic cortical neurons. In human embryonic kidney (HEK293T) cells which expressed SCN5A, LCS attenuated the peak amplitude of INa, in a concentration-dependent fashion. The unique effects of LCS on NaV currents presented here may contribute to its in vivo modulation of cellular excitability.
AB - The effect of lacosamide (LCS), a functionalized molecule with anti-convulsant properties, on ion channels was investigated, with the aid of patch clamp technology and simulation modeling. In NSC-34 neuronal cells, LCS was found to block voltage-gated Na+ current (INa) in a frequency- and concentration-dependent manner. With the two-step voltage protocol, a minimal change in the steady-state inactivation of INa was found in the presence of LCS. However, with repetitive stimulation, the pulse-to-pulse reduction in peak current was shown to be exponential, with a rate linearly related to both the inter-stimulus interval and the LCS concentration. In addition, the frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of NaV channels harboring either an accessible or an inaccessible binding site. LCS also increased the dimension of inactivation space of NaV-channel states, thereby producing the adaptive response of neurons to previous firing. LCS (30μM) had no effects on the non-inactivating component of INa, while it slightly decreased the amplitude of delayed-rectifier K+ current. Moreover, LCS suppressed the peak amplitude of INa in embryonic cortical neurons. In human embryonic kidney (HEK293T) cells which expressed SCN5A, LCS attenuated the peak amplitude of INa, in a concentration-dependent fashion. The unique effects of LCS on NaV currents presented here may contribute to its in vivo modulation of cellular excitability.
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U2 - 10.1016/j.neuroscience.2014.12.026
DO - 10.1016/j.neuroscience.2014.12.026
M3 - Article
C2 - 25534720
AN - SCOPUS:84920918570
SN - 0306-4522
VL - 287
SP - 125
EP - 136
JO - Neuroscience
JF - Neuroscience
ER -