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Ion Channels and Neurological Disease
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Ion Channels and Neurological Disease

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Pharmaceutical Science".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 18275

Special Issue Editor

Dr. Carlo Musio

E-Mail Website
Guest Editor
Institute of Biophysics (IBF), Trento Unit, National Research Council (CNR), Via Sommarive 18, 38123 Trento, Italy
Interests: ion channels; neurobiophysics; neuronal activity; neurodegenerative disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to this Special Issue in Life on the topic "Ion Channels and Neurological Disease".

Ion channels are key elements in the control of membrane physiology and neurotransmission as ionic fluxes assure the neuronal signal propagation across and between neurons through synaptic transmission. Pathophysiology of ion channels may originate from either mutations of gene-encoding components of the channel structure (channelopathy) or secondary dysfunctions—both conditions affect intrinsic excitability in the cell and synaptic functions leading to pathophysiological signs of diseases. Most of the currently known neurodegenerative diseases (NDDs) report alterations in neuronal excitability due to dysfunction of molecular and/or functional features in ion channels. In the majority of NDDs, the pathogenic role of ion channels has been widely demonstrated either for channelopathies or secondary dysfunction. Nevertheless, the link between ion channel alterations underlying neuronal excitability and disease onset has been neglected in some disorders, while for others, research is increasing rapidly.

The aim of this Special Issue is to provide new achievements in the research on pathophysiological changes and structural altered phenotypes in ion channel misfunction. A particular interest could be addressed to drug screening and targeting in order to propose putative therapeutic avenues (including also nutraceutics and/or ethnopharmacology) that can be developed to treat or alleviate these incurable diseases. Multi- and inter-disciplinary research contributions, possibly combining structural, functional, and pharmacological approaches with different methods/techniques, including clinical ones, will be greatly appreciated.

Dr. Carlo Musio
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ion channels
  • neurodegenerative diseases
  • neurodegeneration
  • cellular and animal models
  • neuronal excitability
  • neuronal activity
  • structural and functional correlates
  • computational modeling
  • pathophysiology and pathogenesis
  • channelopaties
  • altered currents
  • neuropharmacology and ethnopharmacology
  • drug screening, delivery and targeting
  • pharmacological treatments
  • molecular therapeutic options
  • neuroprotection

Related Special Issue

Published Papers (10 papers)

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Research

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31 pages, 5504 KiB  
Article
Familial Alzheimer’s Disease Neurons Bearing Mutations in PSEN1 Display Increased Calcium Responses to AMPA as an Early Calcium Dysregulation Phenotype
by Helena Targa Dias Anastacio, Natalie Matosin and Lezanne Ooi
Life 2024, 14(5), 625; https://doi.org/10.3390/life14050625 - 12 May 2024
Viewed by 294
Abstract
Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, [...] Read more.
Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca2+) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca2+ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca2+ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca2+ and glutamate signaling as an early phenotype of FAD. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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13 pages, 3522 KiB  
Article
Nucleoporin Nup358 Downregulation Tunes the Neuronal Excitability in Mouse Cortical Neurons
by Vladimir A. Martínez-Rojas, Francesca Pischedda, Isabel Romero-Maldonado, Bouchra Khalaf, Giovanni Piccoli, Paolo Macchi and Carlo Musio
Life 2023, 13(9), 1791; https://doi.org/10.3390/life13091791 - 22 Aug 2023
Viewed by 846
Abstract
Nucleoporins (NUPs) are proteins that comprise the nuclear pore complexes (NPCs). The NPC spans the nuclear envelope of a cell and provides a channel through which RNA and proteins move between the nucleus and the cytoplasm and vice versa. NUP and NPC disruptions [...] Read more.
Nucleoporins (NUPs) are proteins that comprise the nuclear pore complexes (NPCs). The NPC spans the nuclear envelope of a cell and provides a channel through which RNA and proteins move between the nucleus and the cytoplasm and vice versa. NUP and NPC disruptions have a great impact on the pathophysiology of neurodegenerative diseases (NDDs). Although the downregulation of Nup358 leads to a reduction in the scaffold protein ankyrin-G at the axon initial segment (AIS) of mature neurons, the function of Nup358 in the cytoplasm of neurons remains elusive. To investigate whether Nup358 plays any role in neuronal activity, we downregulated Nup358 in non-pathological mouse cortical neurons and measured their active and passive bioelectrical properties. We identified that Nup358 downregulation is able to produce significant modifications of cell-membrane excitability via voltage-gated sodium channel kinetics. Our findings suggest that Nup358 contributes to neuronal excitability through a functional stabilization of the electrical properties of the neuronal membrane. Hypotheses will be discussed regarding the alteration of this active regulation as putatively occurring in the pathophysiology of NDDs. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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16 pages, 3544 KiB  
Article
GABAB Receptors Tonically Inhibit Motoneurons and Neurotransmitter Release from Descending and Primary Afferent Fibers
by Ximena Delgado-Ramírez, Nara S. Alvarado-Cervantes, Natalie Jiménez-Barrios, Guadalupe Raya-Tafolla, Ricardo Felix, Vladimir A. Martínez-Rojas and Rodolfo Delgado-Lezama
Life 2023, 13(8), 1776; https://doi.org/10.3390/life13081776 - 20 Aug 2023
Cited by 1 | Viewed by 1032
Abstract
Motoneurons receive thousands of excitatory and inhibitory synapses from descending tracts and primary afferent fibers. The excitability of these neurons must be precisely regulated to respond adequately to the requirements of the environment. In this context, GABAA and GABAB receptors regulate [...] Read more.
Motoneurons receive thousands of excitatory and inhibitory synapses from descending tracts and primary afferent fibers. The excitability of these neurons must be precisely regulated to respond adequately to the requirements of the environment. In this context, GABAA and GABAB receptors regulate motoneuron synaptic strength. GABAA and GABAB receptors are expressed on primary afferent fibers and motoneurons, while in the descending afferent fibers, only the GABAB receptors are expressed. However, it remains to be known where the GABA that activates them comes from since the GABAergic interneurons that make axo-axonic contacts with primary afferents have yet to be identified in the descending afferent terminals. Thus, the main aim of the present report was to investigate how GABAB receptors functionally modulate synaptic strength between Ia afferent fibers, excitatory and inhibitory descending fibers of the dorsolateral funiculus, and spinal motoneurons. Using intracellular recordings from the spinal cord of the turtle, we provide evidence that the GABAB receptor antagonist, CGP55845, not only prevents baclofen-induced depression of EPSPs but also increases motoneuron excitability and enhances the synaptic strength between the afferent fibers and motoneurons. The last action of CGP55845 was similar in excitatory and inhibitory descending afferents. Interestingly, the action of baclofen was more intense in the Ia primary afferents than in the descending afferents. Even more, CGP55845 reversed the EPSP depression induced by the increased concentration of ambient GABA produced by interneuron activation and GABA transporter blockade. Immunofluorescence data corroborated the expression of GABAB receptors in the turtle’s spinal cord. These findings suggest that GABAB receptors are extrasynaptic and tonically activated on descending afferent fibers and motoneurons by GABA released from astrocytes and GABAergic interneurons in the cellular microenvironment. Finally, our results also suggest that the antispastic action of baclofen may be due to reduced synaptic strength between descending fibers and motoneurons. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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Review

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13 pages, 1063 KiB  
Review
Bidirectional Regulation of GABAA Reversal Potential in the Adult Brain: Physiological and Pathological Implications
by Haram R. Kim and Marco Martina
Life 2024, 14(1), 143; https://doi.org/10.3390/life14010143 - 19 Jan 2024
Viewed by 1350
Abstract
In physiological conditions, the intracellular chloride concentration is much lower than the extracellular. As GABAA channels are permeable to anions, the reversal potential of GABAA is very close to that of Cl−, which is the most abundant free anion [...] Read more.
In physiological conditions, the intracellular chloride concentration is much lower than the extracellular. As GABAA channels are permeable to anions, the reversal potential of GABAA is very close to that of Cl−, which is the most abundant free anion in the intra- and extracellular spaces. Intracellular chloride is regulated by the activity ratio of NKCC1 and KCC2, two chloride-cation cotransporters that import and export Cl−, respectively. Due to the closeness between GABAA reversal potential and the value of the resting membrane potential in most neurons, small changes in intracellular chloride have a major functional impact, which makes GABAA a uniquely flexible signaling system. In most neurons of the adult brain, the GABAA reversal potential is slightly more negative than the resting membrane potential, which makes GABAA hyperpolarizing. Alterations in GABAA reversal potential are a common feature in numerous conditions as they are the consequence of an imbalance in the NKCC1-KCC2 activity ratio. In most conditions (including Alzheimer’s disease, schizophrenia, and Down’s syndrome), GABAA becomes depolarizing, which causes network desynchronization and behavioral impairment. In other conditions (neonatal inflammation and neuropathic pain), however, GABAA reversal potential becomes hypernegative, which affects behavior through a potent circuit deactivation. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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35 pages, 1304 KiB  
Review
Ion Channels and Ionotropic Receptors in Astrocytes: Physiological Functions and Alterations in Alzheimer’s Disease and Glioblastoma
by Annamaria Lia, Alessandro Di Spiezio, Lorenzo Vitalini, Manuela Tore, Giulia Puja and Gabriele Losi
Life 2023, 13(10), 2038; https://doi.org/10.3390/life13102038 - 11 Oct 2023
Cited by 1 | Viewed by 3705
Abstract
The human brain is composed of nearly one hundred billion neurons and an equal number of glial cells, including macroglia, i.e., astrocytes and oligodendrocytes, and microglia, the resident immune cells of the brain. In the last few decades, compelling evidence has revealed that [...] Read more.
The human brain is composed of nearly one hundred billion neurons and an equal number of glial cells, including macroglia, i.e., astrocytes and oligodendrocytes, and microglia, the resident immune cells of the brain. In the last few decades, compelling evidence has revealed that glial cells are far more active and complex than previously thought. In particular, astrocytes, the most abundant glial cell population, not only take part in brain development, metabolism, and defense against pathogens and insults, but they also affect sensory, motor, and cognitive functions by constantly modulating synaptic activity. Not surprisingly, astrocytes are actively involved in neurodegenerative diseases (NDs) and other neurological disorders like brain tumors, in which they rapidly become reactive and mediate neuroinflammation. Reactive astrocytes acquire or lose specific functions that differently modulate disease progression and symptoms, including cognitive impairments. Astrocytes express several types of ion channels, including K+, Na+, and Ca2+ channels, transient receptor potential channels (TRP), aquaporins, mechanoreceptors, and anion channels, whose properties and functions are only partially understood, particularly in small processes that contact synapses. In addition, astrocytes express ionotropic receptors for several neurotransmitters. Here, we provide an extensive and up-to-date review of the roles of ion channels and ionotropic receptors in astrocyte physiology and pathology. As examples of two different brain pathologies, we focus on Alzheimer’s disease (AD), one of the most diffuse neurodegenerative disorders, and glioblastoma (GBM), the most common brain tumor. Understanding how ion channels and ionotropic receptors in astrocytes participate in NDs and tumors is necessary for developing new therapeutic tools for these increasingly common neurological conditions. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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17 pages, 752 KiB  
Review
Voltage-Gated Na+ Channels in Alzheimer’s Disease: Physiological Roles and Therapeutic Potential
by Timothy J. Baumgartner, Zahra Haghighijoo, Nana A. Goode, Nolan M. Dvorak, Parsa Arman and Fernanda Laezza
Life 2023, 13(8), 1655; https://doi.org/10.3390/life13081655 - 29 Jul 2023
Cited by 1 | Viewed by 1542
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia and is classically characterized by two major histopathological abnormalities: extracellular plaques composed of amyloid beta (Aβ) and intracellular hyperphosphorylated tau. Due to the progressive nature of the disease, it is of the utmost [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia and is classically characterized by two major histopathological abnormalities: extracellular plaques composed of amyloid beta (Aβ) and intracellular hyperphosphorylated tau. Due to the progressive nature of the disease, it is of the utmost importance to develop disease-modifying therapeutics that tackle AD pathology in its early stages. Attenuation of hippocampal hyperactivity, one of the earliest neuronal abnormalities observed in AD brains, has emerged as a promising strategy to ameliorate cognitive deficits and abate the spread of neurotoxic species. This aberrant hyperactivity has been attributed in part to the dysfunction of voltage-gated Na+ (Nav) channels, which are central mediators of neuronal excitability. Therefore, targeting Nav channels is a promising strategy for developing disease-modifying therapeutics that can correct aberrant neuronal phenotypes in early-stage AD. This review will explore the role of Nav channels in neuronal function, their connections to AD pathology, and their potential as therapeutic targets. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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23 pages, 662 KiB  
Review
Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia
by Haoran Huang and Vikram G. Shakkottai
Life 2023, 13(6), 1350; https://doi.org/10.3390/life13061350 - 8 Jun 2023
Cited by 6 | Viewed by 2479
Abstract
In degenerative neurological disorders such as Parkinson’s disease, a convergence of widely varying insults results in a loss of dopaminergic neurons and, thus, the motor symptoms of the disease. Dopamine replacement therapy with agents such as levodopa is a mainstay of therapy. Cerebellar [...] Read more.
In degenerative neurological disorders such as Parkinson’s disease, a convergence of widely varying insults results in a loss of dopaminergic neurons and, thus, the motor symptoms of the disease. Dopamine replacement therapy with agents such as levodopa is a mainstay of therapy. Cerebellar ataxias, a heterogeneous group of currently untreatable conditions, have not been identified to have a shared physiology that is a target of therapy. In this review, we propose that perturbations in cerebellar Purkinje neuron intrinsic membrane excitability, a result of ion channel dysregulation, is a common pathophysiologic mechanism that drives motor impairment and vulnerability to degeneration in cerebellar ataxias of widely differing genetic etiologies. We further propose that treatments aimed at restoring Purkinje neuron intrinsic membrane excitability have the potential to be a shared therapy in cerebellar ataxia akin to levodopa for Parkinson’s disease. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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13 pages, 1064 KiB  
Review
Biophysical Aspects of Neurodegenerative and Neurodevelopmental Disorders Involving Endo-/Lysosomal CLC Cl−/H+ Antiporters
by Maria Antonietta Coppola, Abraham Tettey-Matey, Paola Imbrici, Paola Gavazzo, Antonella Liantonio and Michael Pusch
Life 2023, 13(6), 1317; https://doi.org/10.3390/life13061317 - 2 Jun 2023
Cited by 1 | Viewed by 1309
Abstract
Endosomes and lysosomes are intracellular vesicular organelles with important roles in cell functions such as protein homeostasis, clearance of extracellular material, and autophagy. Endolysosomes are characterized by an acidic luminal pH that is critical for proper function. Five members of the gene family [...] Read more.
Endosomes and lysosomes are intracellular vesicular organelles with important roles in cell functions such as protein homeostasis, clearance of extracellular material, and autophagy. Endolysosomes are characterized by an acidic luminal pH that is critical for proper function. Five members of the gene family of voltage-gated ChLoride Channels (CLC proteins) are localized to endolysosomal membranes, carrying out anion/proton exchange activity and thereby regulating pH and chloride concentration. Mutations in these vesicular CLCs cause global developmental delay, intellectual disability, various psychiatric conditions, lysosomal storage diseases, and neurodegeneration, resulting in severe pathologies or even death. Currently, there is no cure for any of these diseases. Here, we review the various diseases in which these proteins are involved and discuss the peculiar biophysical properties of the WT transporter and how these properties are altered in specific neurodegenerative and neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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19 pages, 776 KiB  
Review
Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders
by Raffaella Barbieri, Mario Nizzari, Ilaria Zanardi, Michael Pusch and Paola Gavazzo
Life 2023, 13(5), 1191; https://doi.org/10.3390/life13051191 - 16 May 2023
Cited by 3 | Viewed by 3075
Abstract
The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system. The encoded proteins [...] Read more.
The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system. The encoded proteins Nav1.1, Nav1.2, Nav1.3, and Nav1.6, respectively, are important players in the initiation and propagation of action potentials and in turn of the neural network activity. In the context of neurological diseases, mutations in the genes encoding Nav1.1, 1.2, 1.3 and 1.6 are responsible for many forms of genetic epilepsy and for Nav1.1 also of hemiplegic migraine. Several pharmacological therapeutic approaches targeting these channels are used or are under study. Mutations of genes encoding VGSCs are also involved in autism and in different types of even severe intellectual disability (ID). It is conceivable that in these conditions their dysfunction could indirectly cause a certain level of neurodegenerative processes; however, so far, these mechanisms have not been deeply investigated. Conversely, VGSCs seem to have a modulatory role in the most common neurodegenerative diseases such as Alzheimer’s, where SCN8A expression has been shown to be negatively correlated with disease severity. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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14 pages, 1067 KiB  
Review
“Dirty Dancing” of Calcium and Autophagy in Alzheimer’s Disease
by Hua Zhang and Ilya Bezprozvanny
Life 2023, 13(5), 1187; https://doi.org/10.3390/life13051187 - 15 May 2023
Cited by 2 | Viewed by 1646
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia. There is a growing body of evidence that dysregulation in neuronal calcium (Ca2+) signaling plays a major role in the initiation of AD pathogenesis. In particular, it is well established that [...] Read more.
Alzheimer’s disease (AD) is the most common cause of dementia. There is a growing body of evidence that dysregulation in neuronal calcium (Ca2+) signaling plays a major role in the initiation of AD pathogenesis. In particular, it is well established that Ryanodine receptor (RyanR) expression levels are increased in AD neurons and Ca2+ release via RyanRs is augmented in AD neurons. Autophagy is important for removing unnecessary or dysfunctional components and long-lived protein aggregates, and autophagy impairment in AD neurons has been extensively reported. In this review we discuss recent results that suggest a causal link between intracellular Ca2+ signaling and lysosomal/autophagic dysregulation. These new results offer novel mechanistic insight into AD pathogenesis and may potentially lead to identification of novel therapeutic targets for treating AD and possibly other neurodegenerative disorders. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease)
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