3,3',4,4'-tetrachlorobiphenyl (PCB77) enhances human Kv1.3 channel currents and alters cytokine production.

Polychlorinated biphenyls (PCBs) were once used throughout various industries; however, because of their persistence in the environment, exposure remains a global threat to the environment and human health. The Kv1.3 and Kv1.5 channels have been implicated in the immunotoxicity and cardiotoxicity of PCBs, respectively. We determined whether 3,3',4,4'-tetrachlorobiphenyl (PCB77), a dioxin-like PCB, alters human Kv1.3 and Kv1.5 currents using the Xenopus oocyte expression system. Exposure to 10 nM PCB77 for 15 min enhanced the Kv1.3 current by approximately 30.6%, whereas PCB77 did not affect the Kv1.5 current at concentrations up to 10 nM. This increase in the Kv1.3 current was associated with slower activation and inactivation kinetics as well as right-shifting of the steady-state activation curve. Pretreatment with PCB77 significantly suppressed tumor necrosis factor-α and interleukin-10 production in lipopolysaccharide-stimulated Raw264.7 macrophages. Overall, these data suggest that acute exposure to trace concentrations of PCB77 impairs immune function, possibly by enhancing Kv1.3 currents.

Acute Inhibition of the Human Kv1.5 Channel by H1 Receptor Antagonist Dimenhydrinate: Mode of Action.

Dimenhydrinate, an H1 receptor antagonist, is generally used for the prevention and treatment of nausea and vomiting. However, cardiac arrhythmias have been reported to be associated with the overdose of histamine H1 receptor antagonists, indicating the probable effect of antihistamines on ion channels. By using a two-microelectrode voltage clamp, we have herein studied the electrophysiological effects of dimenhydrinate on the human Kv1.5 channel in the Xenopus oocyte expression system. Dimenhydrinate acutely and reversibly suppressed the amplitudes of the peak and the steady-state current, within 6 min. The inhibitory effect of dimenhydrinate on the peak and the steady-state Kv1.5 currents increased progressively from -10 to +50 mV. At each test voltage, the drug suppressed both the peak and the steady-state currents to a similar extent. When the oocytes were stimulated at the rates of 5- and 30-s intervals, dimenhydrinate-induced a use-dependent blockade of the human Kv1.5 channel. Dimenhydrinate expedited the timecourse of the Kv1.5 channel activation more effectively than the timecourse of its inactivation. However, the activation and inactivation curves of the channel were not altered by the H1 receptor antagonist. In conclusion, we found that dimenhydrinate inhibits the human Kv1.5 channel by changing the channel's activation mode, thereby possibly increasing the possibility of triggering cardiac arrhythmias and affecting atrial fibrillation.

Inhibitory effects of N-methyl-D-aspartate (NMDA) and α1-adrenergic receptor antagonist ifenprodil on human Kv1.5 channel.

Ifenprodil has been known to reduce cardiac contractility and cerebral vasodilation by antagonizing α1-adrenergic and N-methyl D-aspartate receptor-mediated intracellular signals. This study aimed to investigate the direct effect of ifenprodil on the human voltage-gated Kv1.5 channel (hKv1.5) by using a Xenopus oocyte expression system and a two-microelectrode voltage clamp technique. The amplitudes of hKv1.5 currents, including peak and steady state, were suppressed in a concentration-dependent manner (IC50; 43.1 and 35.5 µM, respectively) after 6 min of ifenprodil treatment. However, these effects were ~ 80% reversed by washout, suggesting that ifenprodil directly inhibited the hKv1.5 independent of membrane receptors or intracellular signals. The inhibition rate of steady state showed voltage dependence, wherein the rates increased according to test voltage depolarization. Ifenprodil reduced the time constants of hKv1.5 inactivation but has higher effects on activation. hKv1.5 inhibition by ifenprodil showed use dependency because the drug more rapidly reduced the current at the higher activation frequencies, and subsequent reduction in frequency after high activation frequency caused a partial channel block relief. Therefore, ifenprodil directly blocked the hKv1.5 in an open state and accelerated the time course of the channel inactivation, which provided a biophysical mechanism for the hKv1.5 blocking effects of ifenprodil.

Inhibitory effect of the selective serotonin reuptake inhibitor paroxetine on human Kv1.3 channels.

Paroxetine is one of the most effective selective serotonin reuptake inhibitors used to treat depressive and panic disorders that reduce the viability of human T lymphocytes, in which Kv1.3 channels are highly expressed. We examined whether paroxetine could modulate human Kv1.3 channels acutely and directly with the aim of understanding the biophysical effects and the underlying mechanisms of the drug. Kv1.3 channel proteins were expressed in Xenopus oocytes. Paroxetine rapidly inhibited the steady-state current and peak current of these channels within 6 min in a concentration-dependent manner; IC50s were 26.3 µM and 53.9 µM, respectively, and these effects were partially reversed by washout, which excluded the possibility of genomic regulation. At the same test voltage, paroxetine blockade of the steady-state currents was higher than that of the peak currents, and the inhibition of the steady-state current increased relative to the degree of depolarization. Paroxetine decreased the inactivation time constant in a concentration-dependent manner, but it did not affect the activation time constant, which resulted in the acceleration of intrinsic inactivation without changing ultrarapid activation. Blockade of Kv1.3 channels by paroxetine exhibited more rapid inhibition at higher activation frequencies showing the use-dependency of the blockade. Overall, these results show that paroxetine directly suppresses human Kv1.3 channels in an open state and accelerates the process of steady-state inactivation; thus, we have revealed a biophysical mechanism for possible acute immunosuppressive effects of paroxetine.

Non-dioxin-like polychlorinated biphenyl 19 has distinct effects on human Kv1.3 and Kv1.5 channels.

Polychlorinated biphenyls (PCBs) are persistent and serious organic pollutants and can theoretically form 209 congeners. PCBs can be divided into two categories: dioxin-like (DL) and non-DL (NDL). NDL-PCBs, which lack aryl hydrocarbon receptor affinity, have been shown to perturb the functions of Jurkat T cells, cerebellar granule cells, and uterine cells. Kv1.3 and Kv1.5 channels are important in immune and heart functions, respectively. We investigated the acute effects of 2,2',6-trichlorinated biphenyl (PCB19), an NDL-PCB, on the currents of human Kv1.3 and Kv1.5 channels. PCB19 acutely blocked the Kv1.3 peak currents concentration-dependently with an IC50 of ~2 µM, without changing the steady-state current. The PCB19-induced inhibition of the Kv1.3 peak current occurred rapidly and voltage-independently, and the effect was irreversible, excluding the possibility of genomic regulation. PCB19 increased the time constants of both activation and inactivation of Kv1.3 channels, resulting in the slowing down of both ultra-rapid activation and intrinsic inactivation. However, PCB19 failed to alter the steady-state curves of activation and inactivation. Regarding the Kv1.5 channel, PCB19 affected neither the peak current nor the steady-state current at the same concentrations tested in the Kv1.3 experiments, showing selective inhibition of PCB19 on the Kv1.3 than the Kv1.5. The presented data indicate that PCB19 could acutely affect the human Kv1.3 channel through a non-genomic mechanism, possibly causing toxic effects on various human physiological functions related to the Kv1.3 channel, such as immune and neural systems.