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Voltage-Gated Ion Channels and Human Diseases
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Voltage-Gated Ion Channels and Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: 20 December 2025 | Viewed by 2645

Special Issue Editor

Dr. María A. Gandini

E-Mail Website
Guest Editor
Department of Clinical Neurosciences, Hotchkiss Brain Institute, Calgary Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
Interests: voltage-gated calcium channels; transient potential receptor channels; pain mechanisms

Special Issue Information

Dear Colleagues,

I am pleased to invite you to contribute to this Special Issue focusing on voltage-gated ion channels in human diseases. The number of disorders linked to ion channel defects has significantly increased in recent years. Mutations in the genes coding for these proteins can lead to various conditions affecting the heart, skeletal muscle, and brain, altering the electrical excitability of cells and increasing the risk of symptoms such as cardiac arrhythmia, periodic paralysis, myotonia, seizures, migraines, episodic ataxia, and other diseases.

For this Special Issue, we welcome your original research or review articles on channelopathies, specifically addressing disorders caused by mutations that result in defective ion channel function, regulation, or expression. The goal is to highlight how studying these mutations can enhance our understanding of the mechanistic basis of human disease and emphasize the critical roles of ion channels.

Dr. María A. Gandini
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • channelopathies
  • voltage gated-ion channels
  • human diseases
  • mutations
  • calcium
  • sodium
  • potassium

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Published Papers (4 papers)

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Research

19 pages, 3217 KiB  
Article
Casein Kinase 2 Regulates the Intrinsic Activity of L-Type Calcium Currents in Cardiomyocytes
by Juan Zhao, Marlena Broszczak and Lucie Parent
Int. J. Mol. Sci. 2025, 26(13), 6010; https://doi.org/10.3390/ijms26136010 - 23 Jun 2025
Viewed by 263
Abstract
Heart failure is associated with dysregulation in cellular Ca2+ that could involve sarcolemmal L-type Ca2+ currents (LTCCs). Building on previous observations showing that recombinant CaV1.2 channels are upregulated by phosphorylated calmodulin (CaM) variants, the cellular mechanism(s) underlying this posttranslational [...] Read more.
Heart failure is associated with dysregulation in cellular Ca2+ that could involve sarcolemmal L-type Ca2+ currents (LTCCs). Building on previous observations showing that recombinant CaV1.2 channels are upregulated by phosphorylated calmodulin (CaM) variants, the cellular mechanism(s) underlying this posttranslational modification was investigated in cultured cardiomyocytes. Whole-cell LTCCs decreased by ≈75% after silencing the gene coding for casein kinase 2 (CK2), a constitutively active kinase in cardiomyocytes, or after its pharmacological inhibition. The overexpression of the dominant negative phosphoresistant single, double T79A/S81A, or triple T79A/S81A/S101A CaM variants resulted in a similar inhibition. In contrast, the overexpression of CaM WT or its double T79D/S81D and triple T79D/S81D/S101D phosphomimetic variants curtailed the downregulation of LTCCs caused by CK2 partial knockdown, suggesting that CK2 is responsible for the posttranslational modification of these CaM target residues. Catecholamines, triggering the protein kinase A (PKA) cascade, partially rescued LTCCs treated with siRNA without or after the overexpression of either CaM WT or stimulating CaM phosphomimetic variants. More importantly, they thwarted the negative impact of the phosphoresistant CaM variants, altogether arguing that CK2 and PKA are acting in synergy to regulate the activity of LTCCs. We conclude that CK2-mediated phosphorylation processes exacerbate the Ca2+ load associated with heart failure. Full article
(This article belongs to the Special Issue Voltage-Gated Ion Channels and Human Diseases)
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22 pages, 4290 KiB  
Article
KCNH3 Loss-of-Function Variant Associated with Epilepsy and Neurodevelopmental Delay Enhances Kv12.2 Channel Inactivation
by Christiane K. Bauer, Arne Bilet, Frederike L. Harms and Robert Bähring
Int. J. Mol. Sci. 2025, 26(10), 4631; https://doi.org/10.3390/ijms26104631 - 13 May 2025
Viewed by 386
Abstract
A de novo missense variant in KCNH3 has been identified in a patient with neurological symptoms including seizures. Here, we confirm the previously reported loss-of-function features for the associated Kv12.2 mutant A371V and investigate the underlying mechanism. Loss of function was not rescued [...] Read more.
A de novo missense variant in KCNH3 has been identified in a patient with neurological symptoms including seizures. Here, we confirm the previously reported loss-of-function features for the associated Kv12.2 mutant A371V and investigate the underlying mechanism. Loss of function was not rescued by low temperature during channel biogenesis. Elevated external K+ reduced the rectification of Kv12.2 conductance as predicted by the GHK current equation, allowing the detection of currents mediated by homomeric A371V Kv12.2 channels and a detailed biophysical analysis of the mutant. Compared to wild-type, the voltage dependences of activation and deactivation of A371V Kv12.2 channels were shifted in the positive direction by 15 to 20 mV. Moreover, A371V Kv12.2 channels exhibited accelerated inactivation kinetics combined with a dramatic negative shift in the voltage dependence of inactivation by more than 100 mV. Even in heteromeric wild-type + A371V Kv12.2 channels, inactivation was enhanced, leading to a significant current reduction at physiological potentials. Our Kv12.2 data show similarities to Kv11 channels regarding C-type inactivation and differences regarding the sensitivity to external K+ and pharmacological inhibition of inactivation. The gating modification caused by the A371V amino acid substitution in Kv12.2 renders loss of function voltage-dependent, with a possible impact on neuronal excitability and firing behavior. Full article
(This article belongs to the Special Issue Voltage-Gated Ion Channels and Human Diseases)
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19 pages, 3362 KiB  
Article
The Leucine-Rich Repeat Kinase 2 Variant LRRK2G2019S Up-Regulates L-Type (CaV1.3) Calcium Channel via the CaVβ3 Subunit: Possible Role in the Pathogenesis of Parkinson’s Disease
by Alejandro Sandoval, Alejandra Corzo-López, Paz Duran, Diana Tovar-Soto, Bryan Vargas-Caballero, Valeria Galicia-Saldaña, Ricardo González-Ramírez and Ricardo Felix
Int. J. Mol. Sci. 2025, 26(7), 3229; https://doi.org/10.3390/ijms26073229 - 31 Mar 2025
Viewed by 785
Abstract
Voltage-gated Ca2+ (CaV) channels are transmembrane proteins comprising the pore-forming subunit CaVα1 and the ancillary proteins CaVα2δ and CaVβ. They are expressed in various tissues, including the nervous system, where they [...] Read more.
Voltage-gated Ca2+ (CaV) channels are transmembrane proteins comprising the pore-forming subunit CaVα1 and the ancillary proteins CaVα2δ and CaVβ. They are expressed in various tissues, including the nervous system, where they regulate Ca2+ entry in response to membrane potential changes. The increase in intracellular Ca2+ allows for regulating cell excitability and releasing neurotransmitters, among other cellular events. Leucine-rich repeat kinase 2 (LRRK2) is a serine–threonine kinase involved in vesicular mobilization. Previously, it has been shown that LRRK2 regulates neurotransmission by phosphorylating the CaVβ auxiliary subunit of the CaV2.1 (P/Q-type) presynaptic channels. However, it is unknown whether the kinase can regulate the activity of other CaV channel subtypes, such as CaV1.3 (L-type), which play a significant role in the excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) and whose dysregulation contributes to neurodegeneration in Parkinson’s disease (PD). Here, we found potential phosphorylation sites for LRRK2 in CaVβ3 and examined how these molecules interact. We used immunoprecipitation and electrophysiology in HEK-293 cells expressing recombinant CaV1.3 channels, both with and without wild-type LRRK2 or its LRRK2G2019S mutation, which plays a role in familial PD through a possible gain-of-toxic-function mechanism. Our results show that LRRK2G2019S significantly increases current density through CaV1.3 channels, and this effect depends on the presence of CaVβ3. Site-directed mutagenesis revealed that phosphorylation at S152 in the sequence of CaVβ3 is necessary and sufficient to explain the abnormal regulation of the channels mediated by LRRK2G2019S. These data provide new insights into the molecular regulation that mutant LRRK2 may exert on L-type CaV1.3 channels, which determine pacemaker activity in dopaminergic neurons of the SNc and may, therefore, play a relevant role in the molecular pathophysiology of PD. Full article
(This article belongs to the Special Issue Voltage-Gated Ion Channels and Human Diseases)
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15 pages, 2519 KiB  
Article
A Metabolically Stable Apelin-13 Analog Acting as a Potent ITo Potassium Current Blocker with Potential Benefits for Brugada Syndrome
by Juan Antonio Contreras Vite, Alexandria Tiffinger, Léa Théroux, Nathalie Morin, Mannix Auger-Messier, Pierre-Luc Boudreault, Philippe Sarret, Olivier Lesur and Robert Dumaine
Int. J. Mol. Sci. 2025, 26(6), 2735; https://doi.org/10.3390/ijms26062735 - 18 Mar 2025
Viewed by 615
Abstract
Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique [...] Read more.
Apelin serves as the endogenous ligand for the APJ receptor and enhances cardiac contractility without significantly affecting potassium currents. However, its short in vivo half-life limits clinical application, prompting the development of metabolically stable APJ receptor agonists. This study employed the patch-clamp technique to investigate the effects of the C-terminally modified apelin-13-2Nal derivative (2Nal) on action potential dynamics, rapid sodium (INa), and transient potassium (ITO) currents in rat cardiomyocytes. We discovered that 2Nal prolongs ventricular action potential duration by selectively blocking ITo. Dose-response analysis indicated that 2Nal acts as a partial antagonist of ITO, achieving a maximum blockade of 47%, with an apparent EC50 of 0.3 nM, while not affecting INa. Our lab previously found that an imbalance between ITo and INa currents contributes to the development of cardiac arrhythmias in conditions like Brugada syndrome. Currently, few therapeutic options exist to safely address this imbalance, as sodium channel openers cannot restore it, and most ITo blockers are cardiotoxic. The selective blockade of ITo by 2Nal that we describe here helps restore the balance of electrical currents between ITo and INa. Our study presents a novel, safe partial antagonist of ITo that may help prevent arrhythmias associated with Brugada syndrome. Full article
(This article belongs to the Special Issue Voltage-Gated Ion Channels and Human Diseases)
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