The Impact of Neurotransmitters on the Neurobiology of Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(20), P. 15340 - 15340

Published: Oct. 19, 2023

Neurodegenerative diseases affect millions of people worldwide. result from progressive damage to nerve cells in the brain or peripheral nervous system connections that are essential for cognition, coordination, strength, sensation, and mobility. Dysfunction these functions is associated with Alzheimer's disease, Parkinson's Huntington's Amyotrophic lateral sclerosis, motor neuron disease. In addition these, 50% living HIV develop a spectrum cognitive, motor, and/or mood problems collectively referred as HIV-Associated Neurocognitive Disorders (HAND) despite widespread use combination antiretroviral therapies. Neuroinflammation neurotransmitter systems have pathological correlation play critical role developing neurodegenerative diseases. Each has unique pattern dysregulation system, which been attributed different forms cell-specific neuronal loss. this review, we will focus on discussion regulation dopaminergic cholinergic systems, more commonly disturbed disorders. Additionally, provide evidence hypothesis disturbances neurotransmission contribute loss observed Further, highlight dopamine mediator injury context NeuroHIV. This review need further investigate their etiology

Language: Английский

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Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

Cells, Journal Year: 2024, Volume and Issue: 13(6), P. 474 - 474

Published: March 7, 2024

Parkinson’s disease (PD) is a progressive neurodegenerative characterized by resting tremor, bradykinesia, rigidity, and postural instability that also includes non-motor symptoms such as mood dysregulation. Dopamine (DA) the primary neurotransmitter involved in this disease, but cholinergic imbalance has been implicated. Current intervention PD focused on replenishing central DA, which provides remarkable temporary symptomatic relief does not address neuronal loss progression of disease. It well established nicotinic receptors (nAChRs) can regulate DA release nicotine itself may have neuroprotective effects. Recent studies identified nAChRs nonneuronal cell types, including glial cells, where they inflammatory responses. Given crucial role neuroinflammation dopaminergic degeneration involvement microglia astrocytes response, provide novel therapeutic target prevention and/or treatment PD. In review, following brief discussion PD, we focus cells and, specifically, their pathology treatment.

Language: Английский

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The Role of α7-Nicotinic Acetylcholine Receptors in the Pathophysiology and Treatment of Parkinson’s Disease

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3210 - 3210

Published: March 30, 2025

The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural functional attributes, highlighting therapeutic potential neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic plasticity, modulate inflammatory responses, influence dopamine release, positioning them as promising pharmacological target. Positive allosteric modulators (PAMs) enhance α7-nAChR activity mainly by reducing desensitization, offering superior approach compared with direct agonists. Emerging preclinical studies suggest that activation mitigates dopaminergic neurodegeneration, improves L-dopa-induced dyskinesia, reduces neuroinflammation. Despite findings, clinical trials have yielded mixed results, necessitating further research into optimizing α7-targeted therapies. underscores significance PD pathophysiology highlights future directions for their translational neuroprotection symptomatic relief.

Language: Английский

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Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

Published: Jan. 31, 2024

Parkinson’s disease (PD) is a progressive neurodegenerative characterized by resting tremor, bradykinesia, rigidity, postural instability, that also includes non-motor symptoms such as mood dysregulation. Dopamine (DA) the primary neurotransmitter involved in this disease, but cholinergic imbalance has been implicated. Current intervention PD focused on replenishing central DA, which provides remarkable temporary symptomatic relief does not address neuronal losss and progression of disease. It well established nicotinic receptors (nAChRs) can regulate DA release nicotine itself may have neuroprotective effects. Recent studies identified nAChRs nonneuronal cell types including glial cells, where they inflammatory responses. Given crucial role neuroinflammation dopaminergic degeneration, involvement microglia astrocytes response, provide novel therapeutic target prevention and/or treatment PD. In review, following brief discussion PD, we focus cells specifically their pathology treatment.

Language: Английский

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The role of ion channels in T cell function and disease

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 29, 2023

T lymphocytes (T cells) are an important sub-group of cells in our immune system responsible for cell-mediated adaptive responses and maintaining homeostasis. Abnormalities cell function, lead the way to persistence infection, impaired immunosurveillance, lack suppression cancer growth, autoimmune diseases. Ion channels play a critical role regulation signaling cellular function often overlooked understudied. Little is known about ion "channelome" interaction cells. This review aims summarize published data on impact disease. The importance health disease plus fact they easily accessible by virtue being expressed surface plasma membranes makes them excellent drug targets.

Language: Английский

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Vestibular modulation by stimulant derivatives in a pentameric ligand‐gated ion channel

British Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Allosteric modulation of pentameric ligand-gated ion channels (pLGICs) are critical for the action neurotransmitters and many psychoactive drugs. However, details their modulatory mechanisms remain unclear, especially beyond orthosteric neurotransmitter-binding sites. The recently reported prokaryotic symbiont Tevnia jerichonana channel (sTeLIC), a pH-gated homologue eukaryotic receptors in pLGIC family, is thought to be modulated by aromatic compounds via relatively uncharacterised site extracellular vestibule. We have characterised effects psychostimulant derivatives on sTeLIC using two-electrode voltage-clamp electrophysiology presence absence engineered mutations, determined X-ray cryo-EM structures both closed open states. shown that sensitive potentiation several amphiphilic compounds, which preferentially bind vestibular pocket contracted open-state domain. This work provides detailed structure-function mechanism allosteric noncanonical ligand site, with potential conservation channels.

Language: Английский

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Assessing the nicotinic acetylcholine receptor-mediated enantioselective neurotoxicity of a neonicotinoid-like pollutant, chiral sulfoxaflor: Insight from the two asymmetric centers

Journal of Hazardous Materials, Journal Year: 2025, Volume and Issue: 494, P. 138468 - 138468

Published: May 2, 2025

Language: Английский

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Nicotinic regulation of microglia: potential contributions to addiction

Journal of Neural Transmission, Journal Year: 2023, Volume and Issue: 131(5), P. 425 - 435

Published: Oct. 1, 2023

Language: Английский

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Structural bases for stoichiometry‐selective calcium potentiation of a neuronal nicotinic receptor

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 181(13), P. 1973 - 1992

Published: March 7, 2024

Background and Purpose α4β2 nicotinic acetylcholine (nACh) receptors assemble in two stoichiometric forms, one of which is potentiated by calcium. The sites calcium binding that underpin potentiation are not known. Experimental Approach To identify sites, we applied cryo‐electron microscopy (cryo‐EM) molecular dynamics (MD) simulations to each form the nACh receptor presence ions. test whether identified linked potentiation, generated mutants anionic residues at expressed wild type mutant clonal mammalian fibroblasts, recorded ACh‐elicited single‐channel currents with or without Key Results Both cryo‐EM MD show bound a site between extracellular transmembrane domains α4 subunit (ECD‐TMD site). Substituting alanine for ECD‐TMD abolishes stoichiometry‐selective as monitored patch clamp electrophysiology. Additionally, simulation reveals association interfaces within domain. ECD reduces potentiation. Conclusions Implications Stoichiometry‐selective achieved topographically distinct framed β2 subunits. could result from greater number three rather than results relevant modulation signalling via physiological pathophysiological conditions.

Language: Английский

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Vestibular Modulation by Stimulant Derivatives in a Pentameric Ligand-Gated Ion Channel

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 5, 2024

Abstract Allosteric modulation of pentameric ligand-gated ion channels (pLGICs) is critical to the action neurotransmitters and many psychoactive drugs. However, details their modulatory mechanisms remain unclear, especially beyond orthosteric neurotransmitter-binding sites. The recently reported prokaryotic channel sTeLIC, a pH-gated homolog eukaryotic receptors in pLGIC family, thought be modulated by aromatic compounds via relatively uncharacterized site extracellular vestibule. Here, we show that sTeLIC sensitive potentiation psychostimulant derivatives. By determining new cryo-EM X-ray structures closed open states, testing impact targeted mutations on electrophysiological behavior, several amphiphilic preferentially bind vestibular pocket contracted open-state domain. This work provides detailed structure-function mechanism for allosteric noncanonical lig- site, with potential conservation channels.

Language: Английский

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