Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors

Cherninskyi, Andrii; Storozhuk, Maksim; Maximyuk, Oleksandr; Kulyk, V. B.; Krishtal, O. A.

doi:10.1007/s12264-022-00986-8

Cited by 5 publications

(4 citation statements)

References 239 publications

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“…However, not a single case has been reported so far when the role of ASICs would be critical. This conclusion is supported by the following straightforward observations: ASICs knockout experiments were never lethal [11] , and yet this also may indicate a particular redundancy, and global knockout of the entire family may provide a much-needed clue. The mechanism of vital physiological importance must be dealt by pharmacologists with great caution or should not be affected at all.…”

Section: Intracellular Perfusion: Ca2+ Current Has Been Measuredmentioning

confidence: 79%

OPINION: History and Perspectives of ASICs

Krishtal

2023

BBA Advances

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Section: Intracellular Perfusion: Ca2+ Current Has Been Measuredmentioning

confidence: 79%

OPINION: History and Perspectives of ASICs

Krishtal

2023

BBA Advances

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“…Suramin (a P2 receptor antagonist) prevents microglia activation when injected intrathecally [ 99 , 100 ] Celecoxib has been shown to inhibit the lipopolysaccharide-induced rise in activated microglia in newborn rats [ 101 , 102 ].…”

Section: Glial Therapy In Autism Spectrum Disordermentioning

confidence: 99%

Modelling the Interplay Between Neuron-Glia Cell Dysfunction and Glial Therapy in Autism Spectrum Disorder

Unnisa

Greig

Kamal

2023

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Autism spectrum disorder (ASD) is a complicated, interpersonally defined, static condition of the underdeveloped brain. Although the aetiology of autism remains unclear, disturbance of neuron-glia interactions has lately been proposed as a significant event in the pathophysiology of ASD. In recent years, the contribution of glial cells to autism has been overlooked. In addition to neurons, glial cells play an essential role in mental activities, and a new strategy that emphasises neuron-glia interactions should be applied. Disturbance of neuron-glia connections has lately been proposed as a significant event in the pathophysiology of ASD because aberrant neuronal network formation and dysfunctional neurotransmission are fundamental to the pathology of the condition. In ASD, neuron and glial cell number changes cause brain circuits to malfunction and impact behaviour. A study revealed that reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Recent discoveries also suggest that dysfunction or changes in the ability of microglia to carry out physiological and defensive functions (such as failure in synaptic elimination or aberrant microglial activation) may be crucial for developing brain diseases, especially autism. The cerebellum, white matter, and cortical regions of autistic patients showed significant microglial activation. Reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Replacement of defective glial cells (Cell-replacement treatment), glial progenitor cell-based therapy, and medication therapy (inhibition of microglia activation) are all utilised to treat glial dysfunction. This review discusses the role of glial cells in ASD and the various potential approaches to treating glial cell dysfunction.

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“…The role of ASICs in higher-order activities such as learning and memory [2], and fear conditioning [23] is determined by their involvement in the functioning of synapses in the amygdala, hippocampus, striatum, and cingulate cortex [22]. ASICs also contribute to various diseases [24]. This is not surprising considering that tissue acidosis is a major contributor to neuronal cell death in many neurological diseases and ASICs, namely, subtype ASIC1a, are critical to acidosis-induced brain neuronal damage [25,26].…”

Section: Introductionmentioning

confidence: 99%

“…Pathologies involving ASICs include various pain states [27,28], ischemic stroke [25,29], epileptic seizures [27,30,31] degenerative disorders such as Alzheimer's disease [32], multiple sclerosis [33,34], Parkinson's disease [35], anxiety disorders [23] and even neonatal hyperbilirubinemia [36]. See [22,24,36] for detailed reviews.…”

Section: Introductionmentioning

confidence: 99%

4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors

Platonov,

Maximyuk,

Rayevsky

et al. 2024

IJMS

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Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc. Functional ASICs are homo or heterotrimers formed with (ASIC1–ASIC3) homologous subunits. ASIC1a, a major ASIC isoform in the central nervous system (CNS), possesses an acidic pocket in the extracellular region, which is a key regulator of channel gating. Growing data suggest that ASIC1a channels are a potential therapeutic target for treating a variety of neurological disorders, including stroke, epilepsy and pain. Many studies were aimed at identifying allosteric modulators of ASIC channels. However, the regulation of ASICs remains poorly understood. Using all available crystal structures, which correspond to different functional states of ASIC1, and a molecular dynamics simulation (MD) protocol, we analyzed the process of channel inactivation. Then we applied a molecular docking procedure to predict the protein conformation suitable for the amiloride binding. To confirm the effect of its sole active blocker against the ASIC1 state transition route we studied the complex with another MD simulation run. Further experiments evaluated various compounds in the Enamine library that emerge with a detectable ASIC inhibitory activity. We performed a detailed analysis of the structural basis of ASIC1a inhibition by amiloride, using a combination of in silico approaches to visualize its interaction with the ion pore in the open state. An artificial activation (otherwise, expansion of the central pore) causes a complex modification of the channel structure, namely its transmembrane domain. The output protein conformations were used as a set of docking models, suitable for a high-throughput virtual screening of the Enamine chemical library. The outcome of the virtual screening was confirmed by electrophysiological assays with the best results shown for three hit compounds.

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Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors

Cited by 5 publications

References 239 publications

OPINION: History and Perspectives of ASICs

OPINION: History and Perspectives of ASICs

Modelling the Interplay Between Neuron-Glia Cell Dysfunction and Glial Therapy in Autism Spectrum Disorder

4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors

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