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

Abstract

The non-linear voltage-dependent hysteresis (Hys(V)) of voltage-gated ionic currents can be robustly activated by the isosceles-triangular ramp voltage (Vramp) 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 Vramp. Pirfenidone, an anti-fibrotic drug, decreased the magnitude of Ih’s Hys(V) activated by triangular Vramp, while dexmedetomidine, an agonist of α2-adrenoceptors, effectively suppressed Ih as well as diminished the Hys(V) strength of Ih. Oxaliplatin, a platinum-based anti-neoplastic drug, was noted to enhance the Ih’s Hys(V) strength, which is thought to be linked to the occurrence of neuropathic pain, while honokiol, a hydroxylated biphenyl compound, decreased Ih’s Hys(V). Cell exposure to lutein, a xanthophyll carotenoid, resulted in a reduction of Ih’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 Vramp 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 Vramp. The Hys(V) properties of persistent Na+ current (INa(P)) evoked by triangular Vramp 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 INa(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 INa(P). Taken together, the observed perturbations by these small-molecule modulators on Hys(V) strength in different types of ionic currents evoked during triangular Vramp are expected to influence the functional activities (e.g., electrical behaviors) of different excitable cells in vitro or in vivo.

Characterization in Potent Modulation on Voltage-Gated Na+ Current Exerted by Deltamethrin, a Pyrethroid Insecticide

“…We further compared the effects of Tef, DLT or their combinations with ChloroTx, Dapa, or amiloride on I Na(L) amplitude. ChloroTx was reported to suppress Cl − current, Dapa was an inhibitor of I Na(L) [ 32 , 33 ], and amiloride can attenuate the pyrethroids-stimulated sodium transport [ 16 ]. As summarized in Figure 2 , with continued presence of Tef or DLT, the further exposure to ChloroTx (1 μM) failed to modify their stimulation of I Na(L) .…”

“…Moreover, the subsequent presence of either Dapa (10 μM) or amiloride (10 μM) was able to attenuate Tef- or DLT-mediated increase of I Na(L) effectively. The results prompted us to suggest that either Dapa or amiloride could directly cause an inhibitory effect on the amplitude of I Na(L) observed in GH 3 cells [ 32 , 33 ].…”

“…The nonlinear Hys (V) behavior residing in I Na(P) has been recently disclosed with a figure-of-eight (i.e., -shaped) configuration as current traces were robustly activated by an upright double V ramp (i.e., ascending and descending limbs of triangular V ramp ) [ 33 ]. In this regard, efforts were made to explore if the existence of Tef or DLT could have any different adjustments on the Hys (V) ’s behavior elicited in response to such upright V ramp .…”

“…However, the further application of dapagliflozin (Dapa) or amiloride can effectively attenuate DLT-activated I Na(L) or I Na(P) . Dapa was recently demonstrated to ameliorate Tef-augmented Hys (V) strength of I Na(P) activated by double V ramp [ 33 ]. Therefore, DLT-mediated stimulation of I Na(T) , I Na(L) , and I Na(P) demonstrated herein is unlikely to be attributed to its activation of Cl − current.…”

“…Work in our laboratory has demonstrated the non-equilibrium Hys (V) behavior of I Na(P) activated by the upright isosceles-triangular V ramp [ 33 ]. The results indicated that there was a striking voltage dependence of such V ramp -evoked I Na(P) [ 29 , 33 ].…”