Ethanol Elevates Excitability of Superior Cervical Ganglion Neurons by Inhibiting Kv7 Channels in a Cell Type-Specific and PI(4,5)P2-Dependent Manner.

Kwon-Woo Kim,Keetae Kim,Byung-Chang Suh,Hyosang Lee

doi:10.3390/ijms20184419

Kwon-Woo Kim, Keetae Kim + Show 2 more

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https://doi.org/10.3390/ijms20184419

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Abstract

Alcohol causes diverse acute and chronic symptoms that often lead to critical health problems. Exposure to ethanol alters the activities of sympathetic neurons that control the muscles, eyes, and blood vessels in the brain. Although recent studies have revealed the cellular targets of ethanol, such as ion channels, the molecular mechanism by which alcohol modulates the excitability of sympathetic neurons has not been determined. Here, we demonstrated that ethanol increased the discharge of membrane potentials in sympathetic neurons by inhibiting the M-type or Kv7 channel consisting of the Kv7.2/7.3 subunits, which were involved in determining the membrane potential and excitability of neurons. Three types of sympathetic neurons, classified by their threshold of activation and firing patterns, displayed distinct sensitivities to ethanol, which were negatively correlated with the size of the Kv7 current that differs depending on the type of neuron. Using a heterologous expression system, we further revealed that the inhibitory effects of ethanol on Kv7.2/7.3 currents were facilitated or diminished by adjusting the amount of plasma membrane phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). These results suggested that ethanol and PI(4,5)P2 modulated gating of the Kv7 channel in superior cervical ganglion neurons in an antagonistic manner, leading to regulation of the membrane potential and neuronal excitability, as well as the physiological functions mediated by sympathetic neurons.

Highlights

Alcohol affects diverse physiological functions mediated by the peripheral and central nervous systems [1,2,3] and causes behavioral and psychological symptoms ranging from modest behavioral disinhibition, such as relaxation and motor incoordination [4,5], to severe cognitive dysfunctions, including sedation [6], amnesia [7], hypnosis, and unconsciousness [8]
We demonstrated that ethanol enhanced excitability and inhibited the medium after-hyperpolarization (mAHP) in between plasma membrane PI(4,5)P2 and ethanol in the modulation of IKv7.2/7.3, which might be the moInlte. cJ.uMlaorl
Ethanol promotes the gating of hyperpolarizationactivated cation channels (HCNs) to increase the spontaneous firing of dopaminergic neurons in the hippocampus and ventral tegmental area (VTA) [38,39,40]

Summary

Introduction

Alcohol affects diverse physiological functions mediated by the peripheral and central nervous systems [1,2,3] and causes behavioral and psychological symptoms ranging from modest behavioral disinhibition, such as relaxation and motor incoordination [4,5], to severe cognitive dysfunctions, including sedation [6], amnesia [7], hypnosis, and unconsciousness [8]. As high concentrations of ethanol are required to produce physiological changes, early studies proposed that the effects of ethanol occur through perturbation of membrane lipids [9]. More recent studies have revealed that alcohol modulates the activity of specific target molecules, including enzymes, ion channels, and receptors [9,10]. Ethanol increases the frequency of spontaneous firing in neurons in the ventral tegmental area (VTA) by suppressing Kv7 channel activity [11]. It has been reported that ethanol activates G protein-gated inwardly rectifying potassium (GIRK) channels by binding to the putative alcohol-binding pocket located near the phospholipid-binding site [12]. Ethanol inhibits the Shaw voltage-gated channel, Kv3, by binding to the amphipathic α-helical region of the intracellular S4-S5 linker [13]

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