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

Abstract

Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. However, transmembrane ionic channels perturbed by this compound remain largely unclear, although the agent is thought to alter the gating characteristics of voltage-gated Na+ (NaV) channel current. In this study, we reappraised whether and how it and other related compounds can make any further modifications on voltage-gated Na+ current (INa) in pituitary tumor (GH3) cells. Cell exposure to DLT produced a differential and dose-dependent stimulation of peak (transient, INa(T)) or sustained (late, INa(L)) INa; consequently, the EC50 value required for DLT-stimulated INa(T) or INa(L) was determined to be 11.2 or 2.5 μM, respectively. However, neither the fast nor slow component in the inactivation time constant of INa(T) activated by short depolarizing pulse was changed with the DLT presence; conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, can accentuate INa with a slowing in inactivation time course of the current. The INa(L) augmented by DLT was attenuated by further application of either dapagliflozin (Dapa) or amiloride, but not by chlorotoxin. During pulse train (PT) stimulation, with the Tef or DLT presence, the cumulative inhibition of INa(T) became slowed; moreover, following PT stimuli, a large tail current with a slowly recovering process was observed. Alternatively, during rapid depolarizing pulse, the amplitude of INa(L) and tail INa (INa(Tail)) for each depolarizing pulse became progressively increased by adding DLT, not by Tef. The recovery time constant following PT stimulation with continued presence of Tef or DLT was shortened by further addition of Dapa. The voltage-dependent hysteresis (Hys(V)) of persistent INa was differentially augmented by Tef or DLT. Taken together, the magnitude, gating, frequency dependence, as well as Hys(V) behavior of INa exerted by the presence of DLT or Tef might exert a synergistic impact on varying functional activities of excitable cells in culture or in vivo.

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

“…Na + channels that have been opened in a voltage-dependent manner then shift to an inactive state, resulting in the transient enhancement of I Na . In addition to the voltage dependence of slow I Na inactivation, studies have reported the striking cumulative inhibition of the current activated during pulse train stimulation ( Taddese and Bean, 2002 ; Huang et al, 2015 ; Navarro et al, 2020 ; Lin et al, 2022 ; Wu et al, 2022a ). At present, it remains unclear whether and how CRS can interact with Na V channels to modify the magnitude, gating kinetics, and frequency-dependence of I Na .…”

Ion Channels as a Potential Target in Pharmaceutical Designs

“…Pyrethroids such as DLT and tefluthrin have been shown to modify the gating properties of voltage-gated Na + (Na V ) channels. In a recent paper by Lin et al [ 2 ], the investigators reappraised whether and how DLT and other related compounds could modify the magnitude and gating of I Na in GH 3 cells. DLT exposure produced a differential and dose-dependent stimulation of I Na(T) and I Na(L) ; consequently, the EC 50 value needed for DL-stimulated I Na(T) or I Na(L) was estimated to be 11.2 or 2.5 μM, respectively [ 2 ].…”

“…In a recent paper by Lin et al [ 2 ], the investigators reappraised whether and how DLT and other related compounds could modify the magnitude and gating of I Na in GH 3 cells. DLT exposure produced a differential and dose-dependent stimulation of I Na(T) and I Na(L) ; consequently, the EC 50 value needed for DL-stimulated I Na(T) or I Na(L) was estimated to be 11.2 or 2.5 μM, respectively [ 2 ]. The I Na(L) augmented by DLT was attenuated through the subsequent addition of dapagliflozin or amiloride but not by chlorotoxin.…”

“…Moreover, during rapid the depolarizing pulse with a rate of 40 Hz, the I Na(L) amplitude for each depolarizing pulse and tail I Na following the end of high-frequency repetitive stimuli was progressively increased by adding DLT. The recovery time constant following pulse train stimulation with a continued presence of DLT was drastically increased; however, it could be shortened by the further addition of dapagliflozin [ 2 ]. Collectively, the modifications by DLT and tefluthrin on the magnitude, gating kinetics, frequency dependence, and hysteretic strength of I Na in electrically excitable cells could be different [ 2 ].…”

“…The recovery time constant following pulse train stimulation with a continued presence of DLT was drastically increased; however, it could be shortened by the further addition of dapagliflozin [ 2 ]. Collectively, the modifications by DLT and tefluthrin on the magnitude, gating kinetics, frequency dependence, and hysteretic strength of I Na in electrically excitable cells could be different [ 2 ].…”