Ion Channels and Neurological Disease: 2nd Edition

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

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• 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

• Ion Channels and Neurological Disease in Life (11 articles)

1. Tentative Title: How to pick a neuroprotective drug for cerebral ischemia
Author: Joe Tauskela
Tentative abstract: Human clinical trials in neuroprotection against stroke continue to fail. Shortcomings in the performance of clinical trials and preclinical methodology have largely been addressed, suggesting that recent failures may be due to suboptimal selection of drugs. Work in the author’s laboratory suggests that anti-excitotoxic approaches represent a crucial focus. This review will outline strategies to optimize selection of anti-excitotoxic approaches. Strategies primarily focus on in vitro-based experimental approaches. Evidence is presented demonstrating how this approach has yielded best-in-class peptides neuroprotectants at the in vitro level.

2. Tentative Title: Neuronal and glial alpha 7 nicotinic acetylcholine receptors: role in Alzheimer’s disease pathophysiology
Author: Kerry Rennie
Tentative abstract: Cholinergic projections from the basal forebrain to the cortex and hippocampus play a critical role in cognitive functions, many of which rely on signaling through the alpha 7 nicotinic acetylcholine receptor (a7nAChR). In addition, the a7nAChR is a key component of a cholinergic pathway that regulates neuroinflammation via interaction with astrocytes and microglia.  Both of these functions have implications in AD and may be affected by degenerative changes in the cholinergic basal forebrain that occur early in the pathophysiological course of AD. Furthermore, the alpha 7 nicotinic acetylcholine receptor binds with high affinity to beta amyloid, facilitating its internalization into neurons, and potentially conferring selective vulnerability to neurons expressing a7nAChR. This review article will cover the role of alpha 7 nicotinic acetylcholine receptors in neurons, astrocytes and microglia under normal conditions, summarize changes in the expression or function of the alpha 7 nAChR in neurons and glia in the AD brain, and discuss cell-type specific contributions of alpha 7 nAChR to AD pathology.

3. Tentative Title: Role of Nav1.7 channels in pre-clinical models of pain
Author: Alvaro Yogi, Umberto Banderali, Maria Moreno, Marzia Martina and Balu Chakravarthy
Tentative abstract: To be decided.

4. Tentative Title: FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function
Author: Arman P, Haghighijoo Z, Lupascu C, Goode N, Xue Y, Wang P, Chen H, Singh AK, Antunes DA, Zhou J, Migliore M, and Laezza F
Tentative abstract: Voltage-gated Na+ channels (Nav) are the molecular determinants of action potential initiation and propagation. Among the nine voltage-gated Na+ channel isoforms (Nav1.1-Nav1.9), Nav1.2 and Nav1.6 are of particular interest because of their developmental expression profile throughout the central nervous system (CNS). Although the α-subunit coded by each of the nine isoforms can sufficiently confer transient Na+ currents (INa), in vivo these channels are modulated by auxiliary proteins like intracellular fibroblast growth factor 14 (FGF14) through protein-protein interaction (PPI). Previous studies have identified ZL0177— peptidomimetic derived from a short peptide sequence at the FGF14/Nav1.6 PPI interface—as a functional modulator of Nav1.6-mediated INa. We chose ZL0177 for selectivity studies against Nav1.2 and Nav1.6 and report the results here. Using automated planar patch-clamp electrophysiology, we assessed ZL0177’s functional activity in cells stably expressing either Nav1.2 or Nav1.6. While ZL0177 was found to suppress INa in both Nav1.2- and Nav1.6-expressing cells, some of its effects on the voltage-dependence of activation and steady-state inactivation were isoform-specific and supported by differential docking of the compound to AlphaFold2 structures of the two channel isoforms. Additionally, computational modeling indicates that ZL0177 can modulate Nav1.2 and Nav1.6 in an isoform-specific manner, eliciting phenotypically divergent action potentials. In conclusion, PPI-based modulators of Nav channels may prove to be valuable in understanding the biology of Nav channels and advancing therapeutic strategies for CNS disorders.

5. Tentative title: Ion channel expression in the human microglial cell line (HMC3): are they a good model system to study ion flux?
Author: Marianna Kulka
Tentative Abstract: To be decided.

6. Tentative title: Role of Ion Channels in the Molecular Pathophysiology of Neuropathic Pain.
Author: Ricardo Felix
Tentative Abstract: Voltage-gated ion channels play a crucial role in the pathophysiology of neuropathic pain. Abnormal expression and malfunction of these proteins are key mechanisms underlying the onset and development of the condition. In the case of injuries to the nervous system, an imbalance is generated in the functional expression of these channels that induce peripheral sensitization, increasing cell excitability and pain signals. The present work reviews the main alterations in voltage-dependent ion channels involved in the cellular and molecular pathophysiology of neuropathic pain. In this context, it is well known that different subtypes of sodium channels (Nav) are expressed in peripheral sensory neurons and play a role in detecting and transmitting sensory information. However, some mutations in Nav channels, essentially in Nav1.7, Nav1.8, and Nav1.9, increase their expression and function, leading to neuropathic pain. Likewise, the increase in intracellular calcium levels in damaged neurons facilitates the release of neurotransmitters and pain transmission, mainly through alterations in the expression of voltage-gated calcium (Cav2.2) channels. Furthermore, the expression of Cav3 channels, which contribute to the control of cell excitability, is altered in dorsal root ganglia neurons after nerve injury. It has been reported that the increase, particularly of Cav3.2 channels, contributes to peripheral sensitization and the development of neuropathic pain. Last, several studies have shown changes in potassium (Kv) channel expression in the dorsal root ganglion after nerve injury. Downregulation in the expression of Kv channels, particularly Kv1.2, Kv7/KCNQ, and Kv9.1, also contributes to the development of neuropathic pain. In summary, dysfunction and inappropriate expression of voltage-gated ion channels contribute to neuronal hyperexcitability underlying the onset and maintenance of neuropathic pain. Therefore, a better understanding of the specific role of different voltage-gated ion channels in neuropathic pain provides information regarding the condition and may open new and better therapeutic opportunities.