The inhibitory actions by lacosamide, a functionalized amino acid, on voltage-gated Na+ currents

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)125-136
Number of pages12
JournalNeuroscience
Volume287
DOIs
Publication statusPublished - 2015 Feb 6

Fingerprint

Amino Acids
lacosamide
Neurons
Convulsants
Drug Interactions
Ion Channels
Binding Sites
Technology
Kidney

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

@article{f3f9f25f0a3e4586ae9059c3fd5e8a4a,
title = "The inhibitory actions by lacosamide, a functionalized amino acid, on voltage-gated Na+ currents",
abstract = "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.",
author = "Chin-Wei Huang and Hung, {T. Y.} and Sheng-Nan Wu",
year = "2015",
month = "2",
day = "6",
doi = "10.1016/j.neuroscience.2014.12.026",
language = "English",
volume = "287",
pages = "125--136",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier Limited",

}

The inhibitory actions by lacosamide, a functionalized amino acid, on voltage-gated Na+ currents. / Huang, Chin-Wei; Hung, T. Y.; Wu, Sheng-Nan.

In: Neuroscience, Vol. 287, 06.02.2015, p. 125-136.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The inhibitory actions by lacosamide, a functionalized amino acid, on voltage-gated Na+ currents

AU - Huang, Chin-Wei

AU - Hung, T. Y.

AU - Wu, Sheng-Nan

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.

UR - http://www.scopus.com/inward/record.url?scp=84920918570&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920918570&partnerID=8YFLogxK

U2 - 10.1016/j.neuroscience.2014.12.026

DO - 10.1016/j.neuroscience.2014.12.026

M3 - Article

C2 - 25534720

AN - SCOPUS:84920918570

VL - 287

SP - 125

EP - 136

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

ER -