A Rapid Facilitation of Acid-Sensing Ion Channels Current by Corticosterone in Cultured Hippocampal Neurons

Extracellular acidification has been shown to generate action potentials (APs) in several types of neurons. In this study, we investigated the role of acid-sensing ion channels (ASICs) in acid-induced AP generation in brain neurons. ASICs are neuronal Na+ channels that belong to the epithelial Na+ channel/degenerin family and are transiently activated by a rapid drop in extracellular pH. We compared the pharmacological and biophysical properties of acid-induced AP generation with those of ASIC currents in cultured hippocampal neurons. Our results show that acid-induced AP generation in these neurons is essentially due to ASIC activation. We demonstrate for the first time that the probability of inducing APs correlates with current entry through ASICs. We also show that ASIC activation in combination with other excitatory stimuli can either facilitate AP generation or inhibit AP bursts, depending on the conditions. ASIC-mediated generation and modulation of APs can be induced by extracellular pH changes from 7.4 to slightly <7. Such local extracellular pH values may be reached by pH fluctuations due to normal neuronal activity. Furthermore, in the plasma membrane, ASICs are localized in close proximity to voltage-gated Na+ and K+ channels, providing the conditions necessary for the transduction of local pH changes into electrical signals.

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Acid-sensing ion channels regulate spontaneous inhibitory activity in the hippocampus: possible implications for epilepsy

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0431 ◽

2016 ◽

Vol 371 (1700) ◽

pp. 20150431 ◽

Cited By ~ 13

Author(s):

O. Ievglevskyi ◽

D. Isaev ◽

O. Netsyk ◽

A. Romanov ◽

M. Fedoriuk ◽

...

Keyword(s):

Ion Channels ◽

Hippocampal Neurons ◽

Hippocampal Slices ◽

Synaptic Activity ◽

Mammalian Brain ◽

Strong Increase ◽

Life And Death ◽

Acid Sensing Ion Channels

Acid-sensing ion channels (ASICs) play an important role in numerous functions in the central and peripheral nervous systems ranging from memory and emotions to pain. The data correspond to a recent notion that each neuron and many glial cells of the mammalian brain express at least one member of the ASIC family. However, the mechanisms underlying the involvement of ASICs in neuronal activity are poorly understood. However, there are two exceptions, namely, the straightforward role of ASICs in proton-based synaptic transmission in certain brain areas and the role of the Ca 2+ -permeable ASIC1a subtype in ischaemic cell death. Using a novel orthosteric ASIC antagonist, we have found that ASICs specifically control the frequency of spontaneous inhibitory synaptic activity in the hippocampus. Inhibition of ASICs leads to a strong increase in the frequency of spontaneous inhibitory postsynaptic currents. This effect is presynaptic because it is fully reproducible in single synaptic boutons attached to isolated hippocampal neurons. In concert with this observation, inhibition of the ASIC current diminishes epileptic discharges in a low Mg 2+ model of epilepsy in hippocampal slices and significantly reduces kainate-induced discharges in the hippocampus in vivo . Our results reveal a significant novel role for ASICs. This article is part of the themed issue ‘Evolution brings Ca 2+ and ATP together to control life and death’.

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Pregnenolone Sulfate Activates NMDA Receptor Channels

Physiological Research ◽

10.33549/physiolres.932558 ◽

2013 ◽

pp. 731-736 ◽

Cited By ~ 5

Author(s):

E. ADAMUSOVÁ ◽

O. CAIS ◽

V. VYKLICKÝ ◽

E. KUDOVÁ ◽

H. CHODOUNSKÁ ◽

...

Keyword(s):

Synaptic Plasticity ◽

Ion Channels ◽

Nmda Receptor ◽

Calcium Signaling ◽

Hippocampal Neurons ◽

Hek293 Cells ◽

Independent Effect ◽

Pregnenolone Sulfate ◽

Specific Manner ◽

Cultured Hippocampal Neurons

Pregnenolone sulfate (PS), an endogenously occurring neurosteroid, has been shown to modulate the activity of several neurotransmitter-gated channels, including the NMDA receptor (NMDAR). NMDARs are glutamate-gated ion channels involved in excitatory synaptic transmission, synaptic plasticity, and excitotoxicity. In this study, we analyzed the effects of PS on calcium signaling in cultured hippocampal neurons and HEK293 cells expressing NMDAR. The cells were loaded with the Ca2+ sensor Fura-2. In agreement with previous electrophysiological experiments, PS potentiated the increases in intracellular Ca2+ induced by an exogenous application of glutamate; however, PS also increased intracellular Ca2+ in the absence of exogenous NMDA agonist. The agonist-independent effect of PS was induced in all neurons studied and in HEK293 cells expressing GluN1/GluN2A-B receptors in a neurosteroid-specific manner. We conclude that PS is an endogenous NMDA agonist that activates the GluN1/GluN2A-B receptors.

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VOLATILE ANESTHETICS BLOCK GLUTAMATE ACTIVATED ION CHANNELS IN CULTURED HIPPOCAMPAL NEURONS

Anesthesiology ◽

10.1097/00000542-198909001-00593 ◽

1989 ◽

Vol 71 (Supplement) ◽

pp. A593 ◽

Cited By ~ 6

Author(s):

J. Yang ◽

C. F. Zorumski

Keyword(s):

Ion Channels ◽

Hippocampal Neurons ◽

Volatile Anesthetics ◽

Cultured Hippocampal Neurons

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Potentiation of acid-sensing ion channels by sulfhydryl compounds

AJP Cell Physiology ◽

10.1152/ajpcell.00598.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. C2161-C2174 ◽

Cited By ~ 27

Author(s):

Jun-Hyeong Cho ◽

Candice C. Askwith

Keyword(s):

Ion Channels ◽

Hippocampal Neurons ◽

Chinese Hamster ◽

Transition Metal Ions ◽

Reducing Agents ◽

Sensory Transduction ◽

Patch Clamp Technique ◽

Acid Sensing Ion Channels ◽

The Impact ◽

Sulfhydryl Compounds

The acid-sensing ion channels (ASICs) are voltage-independent ion channels activated by acidic extracellular pH. ASICs play a role in sensory transduction, behavior, and acidotoxic neuronal death, which occurs during stroke and ischemia. During these conditions, the extracellular concentration of sulfhydryl reducing agents increases. We used perforated patch-clamp technique to analyze the impact of sulfhydryls on H+-gated currents from Chinese hamster ovary (CHO) cells expressing human ASIC1a (hASIC1a). We found that hASIC1a currents activated by pH 6.5 were increased almost twofold by the sulfhydryl-containing reducing agents dithiothreitol (DTT) and glutathione. DTT shifted the pH-dose response of hASIC1a toward a more neutral pH (pH0.5 from 6.54 to 6.69) and slowed channel desensitization. The effect of reducing agents on native mouse hippocampal neurons and transfected mouse ASIC1a was similar. We found that the effect of DTT on hASIC1a was mimicked by the metal chelator TPEN, and mutant hASIC1a channels with reduced TPEN potentiation showed reduced DTT potentiation. Furthermore, the addition of DTT in the presence of TPEN did not result in further increases in current amplitude. These results suggest that the effect of DTT on hASIC1a is due to relief of tonic inhibition by transition metal ions. We found that all ASICs examined remained potentiated following the removal of DTT. This effect was reversed by the oxidizing agent DTNB in hASIC1a, supporting the hypothesis that DTT also impacts ASICs via a redox-sensitive site. Thus sulfhydryl compounds potentiate H+-gated currents via two mechanisms, metal chelation and redox modulation of target amino acids.

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