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 α₂-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., ∞) 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.