| Summary: | Sesamin (SSM) and sesamolin (SesA) are the two major furofuran lignans of sesame oil and they have been previously noticed to exert various biological actions. However, their modulatory actions on different types of ionic currents in electrically excitable cells remain largely unresolved. The present experiments were undertaken to explore the possible perturbations of SSM and SesA on different types of ionic currents, e.g., voltage-gated Na<sup>+</sup> currents (<i>I</i><sub>Na</sub>), <i>erg</i>-mediated K<sup>+</sup> currents (<i>I</i><sub>K(erg)</sub>), M-type K<sup>+</sup> currents (<i>I</i><sub>K(M)</sub>), delayed-rectifier K<sup>+</sup> currents (<i>I</i><sub>K(DR)</sub>) and hyperpolarization-activated cation currents (<i>I</i><sub>h</sub>) identified from pituitary tumor (GH<sub>3</sub>) cells. The exposure to SSM or SesA depressed the transient and late components of <i>I</i><sub>Na</sub> with different potencies. The IC<sub>50</sub> value of SSM needed to lessen the peak or sustained <i>I</i><sub>Na</sub> was calculated to be 7.2 or 0.6 μM, while that of SesA was 9.8 or 2.5 μM, respectively. The dissociation constant of SSM-perturbed inhibition on <i>I</i><sub>Na</sub>, based on the first-order reaction scheme, was measured to be 0.93 μM, a value very similar to the IC<sub>50</sub> for its depressant action on sustained <i>I</i><sub>Na</sub>. The addition of SSM was also effective at suppressing the amplitude of resurgent <i>I</i><sub>Na</sub>. The addition of SSM could concentration-dependently inhibit the <i>I</i><sub>K(M)</sub> amplitude with an IC<sub>50</sub> value of 4.8 μM. SSM at a concentration of 30 μM could suppress the amplitude of <i>I</i><sub>K(erg)</sub>, while at 10 μM, it mildly decreased the <i>I</i><sub>K(DR)</sub> amplitude. However, the addition of neither SSM (10 μM) nor SesA (10 μM) altered the amplitude or kinetics of <i>I</i><sub>h</sub> in response to long-lasting hyperpolarization. Additionally, in this study, a modified Markovian model designed for <i>SCN8A</i>-encoded (or Na<sub>V</sub>1.6) channels was implemented to evaluate the plausible modifications of SSM on the gating kinetics of Na<sub>V</sub> channels. The model demonstrated herein was well suited to predict that the SSM-mediated decrease in peak <i>I</i><sub>Na</sub>, followed by increased current inactivation, which could largely account for its favorable decrease in the probability of the open-blocked over open state of Na<sub>V</sub> channels. Collectively, our study provides evidence that highlights the notion that SSM or SesA could block multiple ion currents, such as <i>I</i><sub>Na</sub> and <i>I</i><sub>K(M)</sub>, and suggests that these actions are potentially important and may participate in the functional activities of various electrically excitable cells in vivo.
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