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Life
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Ion Channels and Neurological Disease: 2nd Edition
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Ion Channels and Neurological Disease: 2nd Edition

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

Deadline for manuscript submissions: 31 July 2025 | Viewed by 8490

Special Issue Editors

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
Dr. Marzia Martina

E-Mail Website
Guest Editor
Human Health Therapeutics Research Centre, National Research Council of Canada, 1200 Montreal Road, Building M54, Ottawa, ON K1A 0R6, Canada
Interests: ion channels; neuroscience neurodegenerative diseases; pain; synaptic transmission

Special Issue Information

Dear Colleagues,

The first volume of this Special Issue was a great success, publishing 10 peer-reviewed articles of recognized high scientific value [https://www.mdpi.com/journal/life/special_issues/38L6X14SR5]; therefore, we invite you to publish your research in the second volume of this Special Issue.

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
Dr. Marzia Martina
Guest Editors

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
  • neurological diseases
  • neurodegeneration
  • pain
  • cellular and animal models
  • neuronal excitability
  • neuronal activity
  • synaptic transmission
  • structural and functional correlates
  • computational modeling
  • pathophysiology and pathogenesis
  • channelopathies
  • altered currents
  • neuropharmacology and ethnopharmacology
  • drug screening, delivery, and targeting
  • pharmacological treatments
  • molecular therapeutic options
  • neuroprotection

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Related Special Issue

Published Papers (5 papers)

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Research

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20 pages, 6788 KiB  
Article
Short Lysine-Containing Tripeptide as Analgesic Substance: The Possible Mechanism of Ligand–Receptor Binding to the Slow Sodium Channel
by Vera B. Plakhova, Arina D. Kalinina, Nadezhda A. Boichenko, Dmitriy M. Samosvat, Georgy G. Zegrya, Irina P. Butkevich, Viktor A. Mikhailenko, Valentina A. Penniyaynen, Svetlana A. Podzorova, Roza I. Yagudina, Boris V. Krylov and Ilya V. Rogachevskii
Life 2024, 14(10), 1337; https://doi.org/10.3390/life14101337 - 21 Oct 2024
Viewed by 1213
Abstract
A possible molecular mechanism of the ligand–receptor binding of Ac-Lys-Lys-Lys-NH2 (Ac-KKK-NH2) to the NaV1.8 channel that is responsible for nociceptive signal coding in the peripheral nervous system is investigated by a number of experimental and theoretical techniques. Upon [...] Read more.
A possible molecular mechanism of the ligand–receptor binding of Ac-Lys-Lys-Lys-NH2 (Ac-KKK-NH2) to the NaV1.8 channel that is responsible for nociceptive signal coding in the peripheral nervous system is investigated by a number of experimental and theoretical techniques. Upon Ac-KKK-NH2 application at 100 nM, a significant decrease in the effective charge carried by the NaV1.8 channel activation gating system Zeff is demonstrated in the patch-clamp experiments. A strong Ac-KKK-NH2 analgesic effect at both the spinal and supraspinal levels is detected in vivo in the formalin test. The distances between the positively charged amino groups in the Ac-KKK-NH2 molecule upon binding to the NaV1.8 channel are 11–12 Å, as revealed by the conformational analysis. The blind docking with the NaV1.8 channel has made it possible to locate the Ac-KKK-NH2 binding site on the extracellular side of the voltage-sensing domain VSDI. The Ac-KKK-NH2 amino groups are shown to form ionic bonds with Asp151 and Glu157 and a hydrogen bond with Thr161, which affects the coordinated movement of the voltage sensor up and down, thus modulating the Zeff value. According to the results presented, Ac-KKK-NH2 is a promising candidate for the role of an analgesic medicinal substance that can be applied for pain relief in humans. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease: 2nd Edition)
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17 pages, 4891 KiB  
Article
TMEM9B Regulates Endosomal ClC-3 and ClC-4 Transporters
by Margherita Festa, Maria Antonietta Coppola, Elena Angeli, Abraham Tettey-Matey, Alice Giusto, Irene Mazza, Elena Gatta, Raffaella Barbieri, Alessandra Picollo, Paola Gavazzo, Michael Pusch, Cristiana Picco and Francesca Sbrana
Life 2024, 14(8), 1034; https://doi.org/10.3390/life14081034 - 20 Aug 2024
Cited by 2 | Viewed by 4503
Abstract
The nine-member CLC gene family of Cl− chloride-transporting membrane proteins is divided into plasma membrane-localized Cl− channels and endo-/lysosomal Cl−/H+ antiporters. Accessory proteins have been identified for ClC-K and ClC-2 channels and for the lysosomal ClC-7, but not [...] Read more.
The nine-member CLC gene family of Cl− chloride-transporting membrane proteins is divided into plasma membrane-localized Cl− channels and endo-/lysosomal Cl−/H+ antiporters. Accessory proteins have been identified for ClC-K and ClC-2 channels and for the lysosomal ClC-7, but not the other CLCs. Here, we identified TMEM9 Domain Family Member B (TMEM9B), a single-span type I transmembrane protein of unknown function, to strongly interact with the neuronal endosomal ClC-3 and ClC-4 transporters. Co-expression of TMEM9B with ClC-3 or ClC-4 dramatically reduced transporter activity in Xenopus oocytes and transfected HEK cells. For ClC-3, TMEM9B also induced a slow component in the kinetics of the activation time course, suggesting direct interaction. Currents mediated by ClC-7 were hardly affected by TMEM9B, and ClC-1 currents were only slightly reduced, demonstrating specific interaction with ClC-3 and ClC-4. We obtained strong evidence for direct interaction by detecting significant Förster Resonance Energy Transfer (FRET), exploiting fluorescence lifetime microscopy-based (FLIM-FRET) techniques between TMEM9B and ClC-3 and ClC-4, but hardly any FRET with ClC-1 or ClC-7. The discovery of TMEM9B as a novel interaction partner of ClC-3 and ClC-4 might have important implications for the physiological role of these transporters in neuronal endosomal homeostasis and for a better understanding of the pathological mechanisms in CLCN3- and CLCN4-related pathological conditions. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease: 2nd Edition)
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Review

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43 pages, 2735 KiB  
Review
Voltage-Gated Ion Channels in Neuropathic Pain Signaling
by Ricardo Felix, Alejandra Corzo-Lopez and Alejandro Sandoval
Life 2025, 15(6), 888; https://doi.org/10.3390/life15060888 - 30 May 2025
Viewed by 471
Abstract
Neuropathic pain is a chronic and debilitating disorder of the somatosensory system that affects a significant proportion of the population and is characterized by abnormal responses such as hyperalgesia and allodynia. Voltage-gated ion channels, including sodium (NaV), calcium (CaV), [...] Read more.
Neuropathic pain is a chronic and debilitating disorder of the somatosensory system that affects a significant proportion of the population and is characterized by abnormal responses such as hyperalgesia and allodynia. Voltage-gated ion channels, including sodium (NaV), calcium (CaV), and potassium (KV) channels, play a pivotal role in modulating neuronal excitability and pain signal transmission following nerve injury. This review intends to provide a comprehensive analysis of the molecular and cellular mechanisms by which dysregulation in the expression, localization, and function of specific NaV channel subtypes (mainly NaV1.7 and NaV1.8) and their auxiliary subunits contributes to aberrant neuronal activation, the generation of ectopic discharges, and sensitization in neuropathic pain. Likewise, special emphasis is placed on the crucial role of CaV channels, particularly CaV2.2 and the auxiliary subunit CaVα2δ, whose overexpression increases calcium influx, neurotransmitter release, and neuronal hyperexcitability, thus maintaining persistent pain states. Furthermore, KV channels (particularly KV7 channels) function as brakes on neuronal excitability, and their dysregulation facilitates the development and maintenance of neuropathic pain. Therefore, targeting specific KV channel subtypes to restore their function is also a promising therapeutic strategy for alleviating neuropathic pain symptoms. On the other hand, recent advances in the development of small molecules as selective modulators or inhibitors targeting voltage-gated ion channels are also discussed. These agents have improved efficacy and safety profiles in preclinical and clinical studies by attenuating pathophysiological channel activity and restoring neuronal function. This review seeks to contribute to guiding future research and drug development toward more effective mechanism-based treatments by discussing the molecular mechanisms underlying neuropathic pain and highlighting translational therapeutic opportunities. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease: 2nd Edition)
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33 pages, 1190 KiB  
Review
How to Pick a Neuroprotective Drug in Stroke Without Losing Your Mind?
by Joseph S. Tauskela and Nicolas Blondeau
Life 2025, 15(6), 883; https://doi.org/10.3390/life15060883 - 30 May 2025
Viewed by 441
Abstract
All human clinical trials evaluating neuroprotective therapeutics in cerebral ischemia have failed, casting a pall over the field which has not recovered. Numerous methodological issues in the performance of these trials were identified, with the result that current trials are now subject to [...] Read more.
All human clinical trials evaluating neuroprotective therapeutics in cerebral ischemia have failed, casting a pall over the field which has not recovered. Numerous methodological issues in the performance of these trials were identified, with the result that current trials are now subject to higher degrees of rigor and transparency. Advances in re-canalization technologies now offer the hope that adjunctive neuroprotection can improve patient outcome. The evaluation of neuroprotection in preclinical animal models has also suffered from methodological issues, which has also been addressed, resulting in an improved performance of studies. This leaves the question of how to actually pick the most appropriate neuroprotective therapy for translation. Given the current limitations in resources, and the numerous strategies that have been proposed to take advantage of clinical and preclinical methodological improvements, we suggest that in vitro studies involving subjecting the most sensitive cells—neurons—to oxygen–glucose deprivation (OGD) can be used to resolve among the many possibilities. Specifically, a large body of evidence shows that successive increases in OGD durations (spanning the lethal/supra-lethal continuum) require increasingly ‘strong’ drugs and combinations to adequately protect neurons (criteria not met in clinical trials). Notably, as the OGD duration is lengthened, NMDA receptor (NMDAR) antagonists of increasing potency and dose are required to match this increasing severity. Under supra-lethal OGD conditions, cocktails composed of anti-excitotoxic antagonists with maximal potency and dose are required to achieve neuroprotection. We propose that this approach can serve as a strategy—a neuroprotective framework—to prioritize among the many possibilities that exist for neuroprotective therapeutics for translation. Specifically, utilize the OGD continuum to compare within-, between- and outside-classes of drugs, first alone and then in combinations, to identify the most efficacious drugs (‘head-to-head’ competitions to identify the ‘last man standing’). While the current state of knowledge strongly suggests that anti-excitotoxic approaches are required, this framework allows the integration of testing established and new therapeutics alike. This framework should include new technologies such as multi-electrode arrays (MEAs), which allow the evaluation of adverse effects of drugs alone, as well as if a drug truly provides functional neuroprotection, and not just survival. The neuroprotective framework provides a comprehensive strategy to eliminate ineffectual treatments, leaving only those modalities with the highest therapeutic index to be prioritized for translation. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease: 2nd Edition)
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32 pages, 2124 KiB  
Review
Preclinical Animal Models to Investigate the Role of Nav1.7 Ion Channels in Pain
by Alvaro Yogi, Umberto Banderali, Maria J. Moreno and Marzia Martina
Life 2025, 15(4), 640; https://doi.org/10.3390/life15040640 - 12 Apr 2025
Viewed by 993
Abstract
Chronic pain is a maladaptive neurological disease that remains a major global healthcare problem. Voltage-gated sodium channels (Navs) are major drivers of the excitability of sensory neurons, and the Nav subtype 1.7 (Nav1.7) has been shown to be [...] Read more.
Chronic pain is a maladaptive neurological disease that remains a major global healthcare problem. Voltage-gated sodium channels (Navs) are major drivers of the excitability of sensory neurons, and the Nav subtype 1.7 (Nav1.7) has been shown to be critical for the transmission of pain-related signaling. This is highlighted by demonstrations that gain-of-function mutations in the Nav1.7 gene SCN9A result in various pain pathologies, whereas loss-of-function mutations cause complete insensitivity to pain. A substantial body of evidence demonstrates that chronic neuropathy and inflammation result in an upregulation of Nav1.7, suggesting that this channel contributes to pain transmission and sensation. As such, Nav1.7 is an attractive human-validated target for the treatment of pain. Nonetheless, a lack of subtype selectivity, insufficient efficacy, and adverse reactions are some of the issues that have hindered Nav1.7-targeted drug development. This review summarizes the pain behavior profiles mediated by Nav1.7 reported in multiple preclinical models, outlining the current knowledge of the biophysical, physiological, and distribution properties required for a Nav1.7 inhibitor to produce analgesia. Full article
(This article belongs to the Special Issue Ion Channels and Neurological Disease: 2nd Edition)
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