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Pharmaceuticals
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Effects of Drugs on Ion Channels
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Effects of Drugs on Ion Channels

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 December 2023) | Viewed by 15826

Special Issue Editors

Dr. Ferenc Papp

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Guest Editor
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary
Interests: molecular pharmacology; patch clamp technique; Voltage Clamp Fluorometry; peptide inhibitors; Kv channels; Hv1
Dr. Tibor Gabor Szántó

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Guest Editor
Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, Egyetem ter 1, H-4032 Debrecen, Hungary
Interests: pharmacology; patch clamp; Kv channel gating; clinical aspects of ion channels; blood–brain-penetrating peptide

Special Issue Information

Dear Colleagues,

You are invited to submit original articles that demonstrate the effects of new molecules on ion channels or describe the mechanism of action of known molecules (small molecule compounds as well as peptides) that have yet to be clarified. We also welcome submissions of review articles that summarize the current state of knowledge and help researchers to navigate this field.

Those of us working in this area know that ion channels are involved in almost all physiological processes both in excitable and non-excitable cells, such as generation of action potential, cell proliferation, secretion, or antigen-dependent activation of T lymphocytes. Moreover, tumor cells express a wide variety of ion channels. Because of these, ion channels became attractive targets for drug discovery and design. Most of these molecules modulate the function of ion channels either by opening, activating or inhibiting them. The inhibition of an ion channel current occurs either through direct binding of the drug to the pore preventing the ion flux through the pore, or by binding to specific regions of the ion channels, such as the voltage sensor or the turret region, thereby affecting the conformational changes necessary for activation of the ion channel. Moreover, certain turret blockers may alter the inactivation of ion channels, a process which essentially determines the fraction of channels available to open.

Many ion channel mutations have been associated with diseases such as LQT syndrome, Brugada syndrome, epilepsy, etc., which are called channelopathies. For this reason, one of the most important ultimate goals of ion channel modulator research is to find molecules that may be potential drug candidates, either acting as an inhibitor or as an activator. On the other hand, understanding the factors that regulate gating transitions of ion channels may aid the design of more efficacious drugs with state-dependent binding. Consequently, studies of the drug–ion channel interactions in channels that display inactivation are also necessary and relevant.

For peptide inhibitors the biggest challenge is to penetrate the peptide through the blood–brain barrier. Therefore, the discovery of new peptide inhibitors modified in such a way that they can penetrate the blood–brain barrier is also highly motivated. 

Dr. Ferenc Papp
Dr. Tibor Gabor Szántó
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. Pharmaceuticals 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 2900 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

  • molecular pharmacology
  • ion channel agonist
  • ion channel antagonist
  • peptide inhibitors
  • small molecule blockers

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Published Papers (5 papers)

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Research

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15 pages, 1764 KiB  
Article
5-Chloro-2-Guanidinobenzimidazole (ClGBI) Is a Non-Selective Inhibitor of the Human HV1 Channel
by Tibor G. Szanto, Adam Feher, Eva Korpos, Adrienn Gyöngyösi, Judit Kállai, Beáta Mészáros, Krisztian Ovari, Árpád Lányi, Gyorgy Panyi and Zoltan Varga
Pharmaceuticals 2023, 16(5), 656; https://doi.org/10.3390/ph16050656 - 27 Apr 2023
Cited by 5 | Viewed by 2111
Abstract
5-chloro-2-guanidinobenzimidazole (ClGBI), a small-molecule guanidine derivative, is a known effective inhibitor of the voltage-gated proton (H+) channel (HV1, Kd ≈ 26 μM) and is widely used both in ion channel research and functional biological assays. However, a comprehensive [...] Read more.
5-chloro-2-guanidinobenzimidazole (ClGBI), a small-molecule guanidine derivative, is a known effective inhibitor of the voltage-gated proton (H+) channel (HV1, Kd ≈ 26 μM) and is widely used both in ion channel research and functional biological assays. However, a comprehensive study of its ion channel selectivity determined by electrophysiological methods has not been published yet. The lack of selectivity may lead to incorrect conclusions regarding the role of hHv1 in physiological or pathophysiological responses in vitro and in vivo. We have found that ClGBI inhibits the proliferation of lymphocytes, which absolutely requires the functioning of the KV1.3 channel. We, therefore, tested ClGBI directly on hKV1.3 using a whole-cell patch clamp and found an inhibitory effect similar in magnitude to that seen on hHV1 (Kd ≈ 72 μM). We then further investigated ClGBI selectivity on the hKV1.1, hKV1.4-IR, hKV1.5, hKV10.1, hKV11.1, hKCa3.1, hNaV1.4, and hNaV1.5 channels. Our results show that, besides HV1 and KV1.3, all other off-target channels were inhibited by ClGBI, with Kd values ranging from 12 to 894 μM. Based on our comprehensive data, ClGBI has to be considered a non-selective hHV1 inhibitor; thus, experiments aiming at elucidating the significance of these channels in physiological responses have to be carefully evaluated. Full article
(This article belongs to the Special Issue Effects of Drugs on Ion Channels)
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15 pages, 2312 KiB  
Article
Association between Migraines and Prior Proton Pump Inhibitor Use: A Nested Case-Control Study Using a National Health Screening Cohort
by Ho Suk Kang, So Young Kim, Ji Hee Kim, Eun Soo Kim, Hyo Geun Choi, Hyun Lim, Joo-Hee Kim, Ha Young Park, Nan Young Kim, Sangkyoon Hong, Kyung Chan Choi and Mi Jung Kwon
Pharmaceuticals 2022, 15(11), 1385; https://doi.org/10.3390/ph15111385 - 10 Nov 2022
Cited by 6 | Viewed by 3216
Abstract
The effect of proton pump inhibitor (PPI) use on migraine risk remains controversial. We explored the odds of migraines in relation to prior PPI use and treatment duration. Data from the Korean National Health Insurance Service-Health Screening Cohort (2002–2015) were analyzed in this [...] Read more.
The effect of proton pump inhibitor (PPI) use on migraine risk remains controversial. We explored the odds of migraines in relation to prior PPI use and treatment duration. Data from the Korean National Health Insurance Service-Health Screening Cohort (2002–2015) were analyzed in this nested case-control study involving 28,159 participants with incident migraines and 112,636 controls (1:4 matched by sex, age, income, and residential region). The baseline covariates were balanced by performing propensity score overlap weighting-based adjustments, and the effect of prior PPI use (past vs. current) and treatment duration (<30 and 30–365 days vs. ≥365 days) on incident migraines was evaluated using logistic regression. In past and current PPI users, prior PPI use raised the likelihood of migraines (adjusted odds ratio [95% confidence interval]: 2.56 [2.36–2.79] and 4.66 [4.29–5.06], respectively). Participants who used PPI for <30, 30–365, or ≥365 days exhibited high odds of migraines (2.49 [2.29–2.72], 4.41 [4.05–4.79], and 4.14 [3.77–4.54], respectively). Incident migraines with or without aura also increased independently of PPI use history or duration. In summary, prior PPI use, irrespective of the elapsed time since use and the duration of use, is possibly associated with incident migraines with or without aura. Full article
(This article belongs to the Special Issue Effects of Drugs on Ion Channels)
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14 pages, 2639 KiB  
Article
Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current INa by Lamotrigine; A Potential for Acquired Arrythmias
by Juan Antonio Contreras Vite, Carlos Vega Valle, Happi Biekeu Mbem, Sarah-Maude Boivin and Robert Dumaine
Pharmaceuticals 2022, 15(10), 1208; https://doi.org/10.3390/ph15101208 - 29 Sep 2022
Cited by 5 | Viewed by 2373
Abstract
Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies [...] Read more.
Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies and Brugada syndrome patterns on the electrocardiograms of epileptic patients treated with the drug. Brugada syndrome and conduction disturbance are both associated with alterations of the cardiac sodium current (INa) kinetics and amplitude. In this study, we used the patch clamp technique on cardiomyocytes from epileptic rats to test the hypothesis that Lamotrigine also blocks INa in the heart. We found that Lamotrigine inhibited 60% of INa peak amplitude and reduced cardiac excitability in epileptic rats but had little effect in sham animals. Moreover, Lamotrigine inhibited 67% of INaL and, more importantly, prolonged the action potential refractory period in epileptic animals. Our results suggest that enhanced affinity of Lamotrigine for INa may in part explain the clinical phenotypes observed in epileptic patients. Full article
(This article belongs to the Special Issue Effects of Drugs on Ion Channels)
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Review

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14 pages, 1841 KiB  
Review
Understanding the Physiological Role of Electroneutral Na+-Coupled HCO3− Cotransporter and Its Therapeutic Implications
by Jingjing Wang, Aqeela Zahra, YunFu Wang and Jianping Wu
Pharmaceuticals 2022, 15(9), 1082; https://doi.org/10.3390/ph15091082 - 30 Aug 2022
Cited by 2 | Viewed by 2891
Abstract
Acid–base homeostasis is critical for proper physiological function and pathology. The SLC4 family of HCO3− transmembrane cotransporters is one of the HCO3− transmembrane transport carriers responsible for cellular pH regulation and the uptake or secretion of HCO3− [...] Read more.
Acid–base homeostasis is critical for proper physiological function and pathology. The SLC4 family of HCO3− transmembrane cotransporters is one of the HCO3− transmembrane transport carriers responsible for cellular pH regulation and the uptake or secretion of HCO3− in epithelial cells. NBCn1 (SLC4A7), an electroneutral Na+/HCO3− cotransporter, is extensively expressed in several tissues and functions as a cotransporter for net acid extrusion after cellular acidification. However, the expression and activity level of NBCn1 remain elusive. In addition, NBCn1 has been involved in numerous other cellular processes such as cell volume, cell death/survival balance, transepithelial transport, as well as regulation of cell viability. This review aims to give an inclusive overview of the most recent advances in the research of NBCn1, emphasizing the basic features, regulation, and tissue-specific physiology as well as the development and application of potent inhibitors of NBCn1 transporter in cancer therapy. Research and development of targeted therapies should be carried out for NBCn1 and its associated pathways. Full article
(This article belongs to the Special Issue Effects of Drugs on Ion Channels)
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16 pages, 1791 KiB  
Review
Na+/H+ Exchanger 1, a Potential Therapeutic Drug Target for Cardiac Hypertrophy and Heart Failure
by Huiting Xia, Aqeela Zahra, Meng Jia, Qun Wang, Yunfu Wang, Susan L. Campbell and Jianping Wu
Pharmaceuticals 2022, 15(7), 875; https://doi.org/10.3390/ph15070875 - 15 Jul 2022
Cited by 20 | Viewed by 3864
Abstract
Cardiac hypertrophy is defined as increased heart mass in response to increased hemodynamic requirements. Long-term cardiac hypertrophy, if not counteracted, will ultimately lead to heart failure. The incidence of heart failure is related to myocardial infarction, which could be salvaged by reperfusion and [...] Read more.
Cardiac hypertrophy is defined as increased heart mass in response to increased hemodynamic requirements. Long-term cardiac hypertrophy, if not counteracted, will ultimately lead to heart failure. The incidence of heart failure is related to myocardial infarction, which could be salvaged by reperfusion and ultimately invites unfavorable myocardial ischemia-reperfusion injury. The Na+/H+ exchangers (NHEs) are membrane transporters that exchange one intracellular proton for one extracellular Na+. The first discovered NHE isoform, NHE1, is expressed almost ubiquitously in all tissues, especially in the myocardium. During myocardial ischemia-reperfusion, NHE1 catalyzes increased uptake of intracellular Na+, which in turn leads to Ca2+ overload and subsequently myocardial injury. Numerous preclinical research has shown that NHE1 is involved in cardiac hypertrophy and heart failure, but the exact molecular mechanisms remain elusive. The objective of this review is to demonstrate the potential role of NHE1 in cardiac hypertrophy and heart failure and investigate the underlying mechanisms. Full article
(This article belongs to the Special Issue Effects of Drugs on Ion Channels)
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