Effective Perturbations by Small-Molecule Modulators on Voltage-Dependent Hysteresis of Transmembrane Ionic Currents

The non-linear voltage-dependent hysteresis (Hys((V))) of voltage-gated ionic currents can be robustly activated by the isosceles-triangular ramp voltage (V-ramp) through digital-to-analog conversion. Perturbations on this Hys((V)) behavior play a role in regulating membrane excitability in different excitable cells. A variety of small molecules may influence the strength of Hys((V)) in different types of ionic currents elicited by long-lasting triangular V-ramp. Pirfenidone, an anti-fibrotic drug, decreased the magnitude of I-h's Hys((V)) activated by triangular V-ramp, while dexmedetomidine, an agonist of alpha(2)-adrenoceptors, effectively suppressed I-h as well as diminished the Hys((V)) strength of I-h. Oxaliplatin, a platinum-based anti-neoplastic drug, was noted to enhance the I-h's Hys((V)) strength, which is thought to be linked to the occurrence of neuropathic pain, while honokiol, a hydroxylated biphenyl compound, decreased I-h's Hys((V)). Cell exposure to lutein, a xanthophyll carotenoid, resulted in a reduction of I-h's Hys((V)) magnitude. Moreover, with cell exposure to UCL-2077, SM-102, isoplumbagin, or plumbagin, the Hys((V)) strength of erg-mediated K+ current activated by triangular V-ramp was effectively diminished, whereas the presence of either remdesivir or QO-58 respectively decreased or increased Hys((V)) magnitude of M-type K+ current. Zingerone, a methoxyphenol, was found to attenuate Hys((V)) (with low- and high-threshold loops) of L-type Ca2+ current induced by long-lasting triangular V-ramp. The Hys((V)) properties of persistent Na+ current (I-Na(P)) evoked by triangular V-ramp were characterized by a figure-of-eight (i.e., infinity) configuration with two distinct loops (i.e., low- and high-threshold loops). The presence of either tefluthrin, a pyrethroid insecticide, or t-butyl hydroperoxide, an oxidant, enhanced the Hys((V)) strength of I-Na(P). However, further addition of dapagliflozin can reverse their augmenting effects in the Hys((V)) magnitude of the current. Furthermore, the addition of esaxerenone, mirogabalin, or dapagliflozin was effective in inhibiting the strength of I-Na(P). Taken together, the observed perturbations by these small-molecule modulators on Hys((V)) strength in different types of ionic currents evoked during triangular V-ramp are expected to influence the functional activities (e.g., electrical behaviors) of different excitable cells in vitro or in vivo.