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Ion Channels: Intersection of Structure, Function and Pharmacology
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Ion Channels: Intersection of Structure, Function and Pharmacology

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

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 7641

Special Issue Editor

Dr. Yann Percherancier

E-Mail Website
Guest Editor
IMS Laboratory (CNRS UMR 5218) , Bordeaux University, Talence, France
Interests: ion channel; bioelectromagnetics; molecular pharmacology and regulation; molecular probes design; molecular biology

Special Issue Information

Dear Colleagues, 

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Widely regarded as attractive drug targets for many therapeutic applications, ion channels represent the third-largest class of targets in drug discovery after G-protein coupled receptors and kinases, thus emphasizing their ‘tractable’ nature. Nonetheless, ion channels remain underexploited as drug targets. Historically, providing new drug candidates on ion channels has almost exclusively relied upon screening of compound libraries. The gold standard for evaluating the activity of ion channels is patch-clamp electrophysiology measurements, which is time-consuming and technically challenging. Automated patch-clamp (APC) techniques are rapidly emerging and provide increased throughput for the direct screening of ion channel targets. For high-throughput screening (HTS), indirect readout technologies are often used as an initial screening step, later confirmed by electrophysiological patch-clamp. Most of the time, these techniques rely on fluorescent assays to monitor changes in membrane potential or intracytoplasmic ion concentrations. These technical approaches only address the relationship between ion channel function and pharmacology, which has proven to be largely insufficient. Even worst, many drugs currently on the market are the fruits of serendipity and not high-throughput screening (HTS), thus emphasizing the need to address ion channel pharmacology and drug discovery from a new angle.

At the same time, the structural determination of several voltage-gated, ligand-gated and polymodal ion channels has increased our understanding of ion permeation, which underlies electrical signaling in cells. Computational approaches to study ion channel dynamics and ion channel-ligand interactions blurred the boundary between pharmacology and structural biology. This issue now aims at fostering studies at the intersection of structure, function, and pharmacology of ion channels to unravel new facets of these fascinating membrane proteins and to provide key concepts to guide the rational design of innovative therapeutics.

Dr. Yann Percherancier
Guest Editor

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Keywords

  • ion channels
  • molecular pharmacology
  • structure/function studies
  • drug design
  • gating

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Published Papers (3 papers)

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Research

22 pages, 3101 KiB  
Article
Block of Voltage-Gated Sodium Channels by Aripiprazole in a State-Dependent Manner
by Karl Josef Föhr, Michael Rapp, Michael Fauler, Thomas Zimmer, Bettina Jungwirth and David Alexander Christian Messerer
Int. J. Mol. Sci. 2022, 23(21), 12890; https://doi.org/10.3390/ijms232112890 - 25 Oct 2022
Cited by 5 | Viewed by 2423
Abstract
Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an interaction with ligand- or voltage-gated ion [...] Read more.
Aripiprazole is an atypical antipsychotic drug, which is prescribed for many psychiatric diseases such as schizophrenia and mania in bipolar disorder. It primarily acts as an agonist of dopaminergic and other G-protein coupled receptors. So far, an interaction with ligand- or voltage-gated ion channels has been classified as weak. Meanwhile, we identified aripiprazole in a preliminary test as a potent blocker of voltage-gated sodium channels. Here, we present a detailed analysis about the interaction of aripiprazole with the dominant voltage-gated sodium channel of heart muscle (hNav1.5). Electrophysiological experiments were performed by means of the patch clamp technique at human heart muscle sodium channels (hNav1.5), heterologously expressed in human TsA cells. Aripiprazole inhibits the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state is weak with an extrapolated Kr of about 55 µM. By contrast, the interaction with the inactivated state is strong. The affinities for the fast and slow inactivated state are in the low micromolar range (0.5–1 µM). Kinetic studies indicate that block development for the inactivated state must be described with a fast (ms) and a slow (s) time constant. Even though the time constants differ by a factor of about 50, the resulting affinity constants were nearly identical (in the range of 0.5 µM). Besides this, aripirazole also interacts with the open state of the channel. Using an inactivation deficit mutant, an affinity of about 1 µM was estimated. In summary, aripiprazole inhibits voltage-gated sodium channels at low micromolar concentrations. This property might add to its possible anticancer and neuroprotective properties. Full article
(This article belongs to the Special Issue Ion Channels: Intersection of Structure, Function and Pharmacology)
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19 pages, 2347 KiB  
Article
Physiological Role of ATPase for GABAA Receptor Resensitization
by Sergey A. Menzikov, Danila M. Zaichenko, Aleksey A. Moskovtsev, Sergey G. Morozov and Aslan A. Kubatiev
Int. J. Mol. Sci. 2022, 23(10), 5320; https://doi.org/10.3390/ijms23105320 - 10 May 2022
Cited by 2 | Viewed by 2060
Abstract
γ-Aminobutyric acid type A receptors (GABAARs) mediate primarily inhibitory synaptic transmission in the central nervous system. Following fast-paced activation, which provides the selective flow of mainly chloride (Cl−) and less bicarbonate (HCO3−) ions via the pore, [...] Read more.
γ-Aminobutyric acid type A receptors (GABAARs) mediate primarily inhibitory synaptic transmission in the central nervous system. Following fast-paced activation, which provides the selective flow of mainly chloride (Cl−) and less bicarbonate (HCO3−) ions via the pore, these receptors undergo desensitization that is paradoxically prevented by the process of their recovery, referred to as resensitization. To clarify the mechanism of resensitization, we used the cortical synaptoneurosomes from the rat brain and HEK 293FT cells. Here, we describe the effect of γ-phosphate analogues (γPAs) that mimic various states of ATP hydrolysis on GABAAR-mediated Cl− and HCO3− fluxes in response to the first and repeated application of the agonist. We found that depending on the presence of bicarbonate, opened and desensitized states of the wild or chimeric GABAARs had different sensitivities to γPAs. This study presents the evidence that recovery of neuronal Cl− and HCO3− concentrations after desensitization is accompanied by a change in the intracellular ATP concentration via ATPase performance. The transition between the desensitization and resensitization states was linked to changes in both conformation and phosphorylation. In addition, the chimeric β3 isoform did not exhibit the desensitization of the GABAAR-mediated Cl− influx but only the resensitization. These observations lend a new physiological significance to the β3 subunit in the manifestation of GABAAR resensitization. Full article
(This article belongs to the Special Issue Ion Channels: Intersection of Structure, Function and Pharmacology)
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17 pages, 4652 KiB  
Article
Small Extracellular Vesicles Containing miR-34c Derived from Bone Marrow Mesenchymal Stem Cells Regulates Epithelial Sodium Channel via Targeting MARCKS
by Yu Hua, Aixin Han, Tong Yu, Yapeng Hou, Yan Ding and Hongguang Nie
Int. J. Mol. Sci. 2022, 23(9), 5196; https://doi.org/10.3390/ijms23095196 - 6 May 2022
Cited by 11 | Viewed by 2350
Abstract
Epithelial sodium channel (ENaC) is a pivotal regulator of alveolar fluid clearance in the airway epithelium and plays a key role in the treatment of acute lung injury (ALI), which is mainly composed of the three homologous subunits (α, β and γ). The [...] Read more.
Epithelial sodium channel (ENaC) is a pivotal regulator of alveolar fluid clearance in the airway epithelium and plays a key role in the treatment of acute lung injury (ALI), which is mainly composed of the three homologous subunits (α, β and γ). The mechanisms of microRNAs in small extracellular vesicles (sEVs) derived from mesenchymal stem cell (MSC-sEVs) on the regulation of lung ion transport are seldom reported. In this study, we aimed at investigating whether miR-34c had an effect on ENaC dysfunction induced by lipopolysaccharide and explored the underlying mechanism in this process. Primarily, the effect of miR-34c on lung edema and histopathology changes in an ALI mouse model was investigated. Then the uptake of PKH26-labeled sEVs was observed in recipient cells, and we observed that the overexpression of miR-34c in MSC-sEVs could upregulate the LPS-inhibited γ-ENaC expression. The dual luciferase reporter gene assay demonstrated that myristoylated alanine-rich C kinase substrate (MARCKS) was one of target genes of miR-34c, the protein expression of which was negatively correlated with miR-34c. Subsequently, either upregulating miR-34c or knocking down MARCKS could increase the protein expression of phospho-phosphatidylinositol 3-kinase (p-PI3K) and phospho-protein kinase B (p-AKT), implying a downstream regulation pathway was involved. All of the above suggest that miR-34c in MSC-sEVs can attenuate edematous lung injury via enhancing γ-ENaC expression, at least partially, through targeting MARCKS and activating the PI3K/AKT signaling pathway subsequently. Full article
(This article belongs to the Special Issue Ion Channels: Intersection of Structure, Function and Pharmacology)
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