AUTHOR=Hung Te-Yu , Wu Sheng-Nan , Huang Chin-Wei 

TITLE=Concerted suppressive effects of carisbamate, an anti-epileptic alkyl-carbamate drug, on voltage-gated Na+ and hyperpolarization-activated cation currents

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=17

YEAR=2023

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2023.1159067

DOI=10.3389/fncel.2023.1159067

ISSN=1662-5102

ABSTRACT=<p>Carisbamate (CRS, RWJ-333369) is a new anti-seizure medication. It remains unclear whether and how CRS can perturb the magnitude and/or gating kinetics of membrane ionic currents, despite a few reports demonstrating its ability to suppress voltage-gated Na<sup>+</sup> currents. In this study, we observed a set of whole-cell current recordings and found that CRS effectively suppressed the voltage-gated Na<sup>+</sup> (<italic>I</italic><sub>Na</sub>) and hyperpolarization-activated cation currents (<italic>I</italic><sub>h</sub>) intrinsically in electrically excitable cells (GH<sub>3</sub> cells). The effective IC<sub>50</sub> values of CRS for the differential suppression of transient (<italic>I</italic><sub>Na(T)</sub>) and late <italic>I</italic><sub>Na</sub> (<italic>I</italic><sub>Na(L)</sub>) were 56.4 and 11.4 μM, respectively. However, CRS strongly decreased the strength (i.e., Δarea) of the nonlinear window component of <italic>I</italic><sub>Na</sub> (<italic>I</italic><sub>Na(W)</sub>), which was activated by a short ascending ramp voltage (<italic>V</italic><sub>ramp</sub>); the subsequent addition of deltamethrin (DLT, 10 μM) counteracted the ability of CRS (100 μM, continuous exposure) to suppress <italic>I</italic><sub>Na(W)</sub>. CRS strikingly decreased the decay time constant of <italic>I</italic><sub>Na(T)</sub> evoked during pulse train stimulation; however, the addition of telmisartan (10 μM) effectively attenuated the CRS (30 μM, continuous exposure)-mediated decrease in the decay time constant of the current. During continued exposure to deltamethrin (10 μM), known to be a pyrethroid insecticide, the addition of CRS resulted in differential suppression of the amplitudes of <italic>I</italic><sub>Na(T)</sub> and <italic>I</italic><sub>Na(L)</sub>. The amplitude of <italic>I</italic><sub>h</sub> activated by a 2-s membrane hyperpolarization was diminished by CRS in a concentration-dependent manner, with an IC<sub>50</sub> value of 38 μM. For <italic>I</italic><sub>h</sub>, CRS altered the steady-state <italic>I–V</italic> relationship and attenuated the strength of voltage-dependent hysteresis (Hys<sub>(V)</sub>) activated by an inverted isosceles-triangular <italic>V</italic><sub>ramp</sub>. Moreover, the addition of oxaliplatin effectively reversed the CRS-mediated suppression of Hys<sub>(V)</sub>. The predicted docking interaction between CRS and with a model of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel or between CRS and the hNa<sub>V</sub>1.7 channel reflects the ability of CRS to bind to amino acid residues in HCN or hNa<sub>V</sub>1.7 channel via hydrogen bonds and hydrophobic interactions. These findings reveal the propensity of CRS to modify <italic>I</italic><sub>Na(T)</sub> and <italic>I</italic><sub>Na(L)</sub> differentially and to effectively suppress the magnitude of <italic>I</italic><sub>h</sub>. <italic>I</italic><sub>Na</sub> and <italic>I</italic><sub>h</sub> are thus potential targets of the actions of CRS in terms of modulating cellular excitability.</p>