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 (30 μM) 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.
authors.affiliation: Department of Neurology, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: C-W
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: T-Y
authors.initials: TY
authors.lastname: Hung
authors.affiliation: Department of Physiology, National Cheng Kung University Medical College, Tainan, Taiwan; Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan. Electronic address: snwu@mail.ncku.edu.tw.
authors.forename: S-N
authors.initials: SN
authors.lastname: Wu
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002460:Cell Line; D004558:Electric Stimulation; D006801:Humans; D000078334:Lacosamide; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D061566:Voltage-Gated Sodium Channels / Q000502:physiology*
chemical_list: D000081:Acetamides; D000596:Amino Acids; D000927:Anticonvulsants; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D061566:Voltage-Gated Sodium Channels; D000078334:Lacosamide
keywords: Na(+) current; current inactivation; excitability; lacosamide; use dependence