The inhibitory actions by lacosamide, a functionalized amino acid, on voltage-gated Na+ currents. (26th February 2015)

• Record Type: Journal Article
• Authors: Huang, C.-W.; Hung, T.-Y.; Wu, S.-N.
• Is Part Of: Neuroscience. Volume 287(2015)
• Page Start: 125
• Page End: 136
• Publication Date: 2015-02-26
• Subjects: FBS fetal bovine serum -- HEK293T human embryonic kidney cells -- I–V current–voltage -- LCS lacosamide -- TEA tetraethylammonium chloride -- TTX tetrodotoxin; lacosamide -- Na+ current -- use dependence -- current inactivation -- excitability; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2014.12.026
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: The ionic effect of lacosamide is investigated and simulated. Lacosamide blocks voltage-gated Na + current in a frequency- and concentration-dependent manner in neurons. Lacosamide increases the inactivation space of Na + channel states, shaping the adaptive neuronal response to previous firing. The non-inactivating Na + and delayed-rectifier K + current are not affected by lacosamide. Lacosamide attenuates the Na + current in HEK293T cells expressing SCN5A, in a concentration-dependent fashion. 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 ( I Na ) in a frequency- and concentration-dependent manner. With the two-step voltage protocol, a minimal change in the steady-state inactivation of I Na 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 (30 μM) had no effects on the non-inactivating component of I Na, while it slightly decreased the amplitude of delayed-rectifier K + current. Moreover, LCS suppressed the peak amplitude of I Na in embryonic cortical neurons. In human embryonic kidney (HEK293T) cells which expressed SCN5A, LCS attenuated the peak amplitude of I Na, 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.