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Studies on Proton-Gated Ion Channels: Structural Aspects, Pharmacology and Implications in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: 15 September 2024 | Viewed by 3722

Special Issue Editor


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Guest Editor
1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia
2. Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
Interests: acid-sensing ion channel (ASIC); endogenous neuropeptide; venom peptides; low molecular weight compounds; electrophysiology; signaling; neuroscience; modulator of receptor; inflammation; pain

Special Issue Information

Dear Colleagues,

Proton-Gated Ion Channels are a group of membrane-integrated complexes of protein subunits that are activated via an acidic stimulus, followed by the generation of an inward cation current into the cell. This group primarily includes acid-sensing ion channels (ASIC channels), which are the most sensitive to protons, as well as transient receptor potential (TRP) channels of the TRPV and TRPA subfamilies. Present in the neurons of the central nervous system (NS) and abundantly in the sensory neurons of the peripheral NS, Proton-Gated Ion Channels often play a critical role in various physiological and pathophysiological processes, such as synaptic plasticity, fear and anxiety, nociception and the occurrence of chronic pain, inflammation and hypersensitivity, ischemic neuronal death and other neurodegenerative processes, etc.

This Special Issue, titled “Studies on Proton-Gated Ion Channels: Structural Aspects, Pharmacology and Implications in Health and Disease”, aims to gather contemporary and comprehensive research concerning both Proton-Gated Ion Channels themselves and their exogenous and endogenous modulators, including, but not limited to, the structural and functional aspects and  contributions of these channels to various physiological and pathological processes, as well as the pharmacological potential that the ligands of these channels have in these processes.

Dr. Dmitry I. Osmakov
Guest Editor

Manuscript Submission Information

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Keywords

  • acid-sensing ion channels
  • other proton-gated ion channels
  • modulators of proton-gated ion channels
  • structural-functional analysis
  • animal models
  • cognitive functions
  • inflammatory diseases
  • pain
 

Published Papers (3 papers)

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Research

16 pages, 4148 KiB  
Article
Modulation of TRPV1 and TRPA1 Channels Function by Sea Anemones’ Peptides Enhances the Viability of SH-SY5Y Cell Model of Parkinson’s Disease
by Yuliya S. Kolesova, Yulia Y. Stroylova, Ekaterina E. Maleeva, Anastasia M. Moysenovich, Denis V. Pozdyshev, Vladimir I. Muronetz and Yaroslav A. Andreev
Int. J. Mol. Sci. 2024, 25(1), 368; https://doi.org/10.3390/ijms25010368 - 27 Dec 2023
Viewed by 1058
Abstract
Cellular dysfunction during Parkinson’s disease leads to neuroinflammation in various brain regions, inducing neuronal death and contributing to the progression of the disease. Different ion channels may influence the process of neurodegeneration. The peptides Ms 9a-1 and APHC3 can modulate the function of [...] Read more.
Cellular dysfunction during Parkinson’s disease leads to neuroinflammation in various brain regions, inducing neuronal death and contributing to the progression of the disease. Different ion channels may influence the process of neurodegeneration. The peptides Ms 9a-1 and APHC3 can modulate the function of TRPA1 and TRPV1 channels, and we evaluated their cytoprotective effects in differentiated to dopaminergic neuron-like SH-SY5Y cells. We used the stable neuroblastoma cell lines SH-SY5Y, producing wild-type alpha-synuclein and its mutant A53T, which are prone to accumulation of thioflavin-S-positive aggregates. We analyzed the viability of cells, as well as the mRNA expression levels of TRPA1, TRPV1, ASIC1a channels, alpha-synuclein, and tyrosine hydroxylase after differentiation of these cell lines using RT-PCR. Overexpression of alpha-synuclein showed a neuroprotective effect and was accompanied by a reduction of tyrosine hydroxylase expression. A mutant alpha-synuclein A53T significantly increased the expression of the pro-apoptotic protein BAX and made cells more susceptible to apoptosis. Generally, overexpression of alpha-synuclein could be a model for the early stages of PD, while expression of mutant alpha-synuclein A53T mimics a genetic variant of PD. The peptides Ms 9a-1 and APHC3 significantly reduced the susceptibility to apoptosis of all cell lines but differentially influenced the expression of the genes of interest. Therefore, these modulators of TRPA1 and TRPV1 have the potential for the development of new therapeutic agents for neurodegenerative disease treatment. Full article
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16 pages, 3234 KiB  
Article
Dual Modulator of ASIC Channels and GABAA Receptors from Thyme Alters Fear-Related Hippocampal Activity
by Aleksandr P. Kalinovskii, Anton P. Pushkarev, Anastasia D. Mikhailenko, Denis S. Kudryavtsev, Olga A. Belozerova, Vladimir I. Shmygarev, Oleg N. Yatskin, Yuliya V. Korolkova, Sergey A. Kozlov, Dmitry I. Osmakov, Alexander Popov and Yaroslav A. Andreev
Int. J. Mol. Sci. 2023, 24(17), 13148; https://doi.org/10.3390/ijms241713148 - 24 Aug 2023
Cited by 1 | Viewed by 1040
Abstract
Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory [...] Read more.
Acid-sensing ion channels (ASICs) are proton-gated ion channels that mediate nociception in the peripheral nervous system and contribute to fear and learning in the central nervous system. Sevanol was reported previously as a naturally-occurring ASIC inhibitor from thyme with favorable analgesic and anti-inflammatory activity. Using electrophysiological methods, we found that in the high micromolar range, the compound effectively inhibited homomeric ASIC1a and, in sub- and low-micromolar ranges, positively modulated the currents of α1β2γ2 GABAA receptors. Next, we tested the compound in anxiety-related behavior models using a targeted delivery into the hippocampus with parallel electroencephalographic measurements. In the open field, 6 µM sevanol reduced both locomotor and θ-rhythmic activity similar to GABA, suggesting a primary action on the GABAergic system. At 300 μM, sevanol markedly suppressed passive avoidance behavior, implying alterations in conditioned fear memory. The observed effects could be linked to distinct mechanisms involving GABAAR and ASIC1a. These results elaborate the preclinical profile of sevanol as a candidate for drug development and support the role of ASIC channels in fear-related functions of the hippocampus. Full article
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12 pages, 2186 KiB  
Article
Possible Compensatory Role of ASICs in Glutamatergic Synapses
by Konstantin K. Evlanenkov, Arseniy S. Zhigulin and Denis B. Tikhonov
Int. J. Mol. Sci. 2023, 24(16), 12974; https://doi.org/10.3390/ijms241612974 - 19 Aug 2023
Cited by 2 | Viewed by 670
Abstract
Proton-gated channels of the ASIC family are widely distributed in central neurons, suggesting their role in common neurophysiological functions. They are involved in glutamatergic neurotransmission and synaptic plasticity; however, the exact function of these channels remains unclear. One problem is that acidification of [...] Read more.
Proton-gated channels of the ASIC family are widely distributed in central neurons, suggesting their role in common neurophysiological functions. They are involved in glutamatergic neurotransmission and synaptic plasticity; however, the exact function of these channels remains unclear. One problem is that acidification of the synaptic cleft due to the acidic content of synaptic vesicles has opposite effects on ionotropic glutamate receptors and ASICs. Thus, the pH values required to activate ASICs strongly inhibit AMPA receptors and almost completely inhibit NMDA receptors. This, in turn, suggests that ASICs can provide compensation for post-synaptic responses in the case of significant acidifications. We tested this hypothesis by patch-clamp recordings of rat brain neuron responses to acidifications and glutamate receptor agonists at different pH values. Hippocampal pyramidal neurons have much lower ASICs than glutamate receptor responses, whereas striatal interneurons show the opposite ratio. Cortical pyramidal neurons and hippocampal interneurons show similar amplitudes in their responses to acidification and glutamate. Consequently, the total response to glutamate agonists at different pH levels remains rather stable up to pH 6.2. Besides these pH effects, the relationship between the responses mediated by glutamate receptors and ASICs depends on the presence of Mg2+ and the membrane voltage. Together, these factors create a complex picture that provides a framework for understanding the role of ASICs in synaptic transmission and synaptic plasticity. Full article
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