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Pharmaceuticals
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Ion Channels: Current Pharmacological Challenges
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Ion Channels: Current Pharmacological Challenges

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

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 25643

Special Issue Editors

Dr. Balazs Horvath

E-Mail Website
Guest Editor
1. Department of Physiology, University of Debrecen, Debrecen, Hungary
2. Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary
Interests: myocardium; cardiac ion channels; ionic currents; late sodium current; cardiac action potential; cellular calcium homeostasis; signal transduction; cardiac arrhythmia
Dr. Péter P. Nánási

E-Mail Website
Guest Editor
Department of Physiology, University of Debrecen, Debrecen, Hungary
Interests: myocardium; cardiac ion channels; ionic currents; late sodium current; cardiac action potential; cellular calcium homeostasis; signal transduction; cardiac arrhythmia

Special Issue Information

Dear Colleagues,

Ion channels are pore-forming transmembrane proteins that differ by their structure, their ion specificity, and their mode of activation and action. There are over 300 genes in the human genome encoding ion channel subunits. They participate in almost every biological process. Because of their fundamental importance, they also play a role in many pathophysiologies, therefore, becoming therapeutic targets for treating several diseases. Despite focused efforts in the past, approved drugs are available for only less than 10% of this protein class, creating a significant, yet unexploited niche for drug discovery.

The development of ion channel targeting drugs has always been difficult. Among the many challenges associated with molecular drug discovery are validating new ion channel protein targets and identifying reasonable lead compounds. This is at least partly due to limitations in high-throughput screening technologies that support target validation and lead optimization.

Until recently, most ion channel drug development has focused on small molecule and peptide modulators. An emerging and very promising way of targeting ion channels is monoclonal antibodies.

In this Special Issue of Pharmaceuticals, you can find updates on how the drug development industry is trying to tackle some of the current pharmacological challenges associated with ion channels.

Dr. Balazs Horvath
Dr. Péter P. Nánási
Guest Editors

Manuscript Submission Information

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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.

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Keywords

  • ion channel
  • subunit
  • therapeutic target
  • drug discovery
  • drug development
  • channelopathy

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Published Papers (7 papers)

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Research

Jump to: Review

15 pages, 4963 KiB  
Article
The Inhibition of the Small-Conductance Ca2+-Activated Potassium Channels Decreases the Sinus Node Pacemaking during Beta-Adrenergic Activation
by Gergő Bitay, Noémi Tóth, Szilvia Déri, Jozefina Szlovák, Zsófia Kohajda, András Varró and Norbert Nagy
Pharmaceuticals 2022, 15(3), 313; https://doi.org/10.3390/ph15030313 - 4 Mar 2022
Cited by 1 | Viewed by 2547
Abstract
Sinus pacemaking is based on tight cooperation of intracellular Ca2+ handling and surface membrane ion channels. An important player of this synergistic crosstalk could be the small-conductance Ca2+-activated K+-channel (ISK) that could contribute to the sinoatrial [...] Read more.
Sinus pacemaking is based on tight cooperation of intracellular Ca2+ handling and surface membrane ion channels. An important player of this synergistic crosstalk could be the small-conductance Ca2+-activated K+-channel (ISK) that could contribute to the sinoatrial node (SAN) pacemaking driven by the intracellular Ca2+ changes under normal conditions and beta-adrenergic activation, however, the exact role is not fully clarified. SK2 channel expression was verified by immunoblot technique in rabbit SAN cells. Ionic currents and action potentials were measured by patch-clamp technique. The ECG R-R intervals were obtained by Langendorff-perfusion method on a rabbit heart. Apamin, a selective inhibitor of SK channels, was used during the experiments. Patch-clamp experiments revealed an apamin-sensitive current. When 100 nM apamin was applied, we found no change in the action potential nor in the ECG R-R interval. In experiments where isoproterenol was employed, apamin increased the cycle length of the SAN action potentials and enhanced the ECG R-R interval. Apamin did not amplify the cycle length variability or ECG R-R interval variability. Our data indicate that ISK has no role under normal condition, however, it moderately contributes to the SAN automaticity under beta-adrenergic activation. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
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16 pages, 2380 KiB  
Article
SK Channels Modulation Accelerates Equilibrium Recovery in Unilateral Vestibular Neurectomized Rats
by Brahim Tighilet, Audrey Bourdet, David Péricat, Elise Timon-David, Guillaume Rastoldo and Christian Chabbert
Pharmaceuticals 2021, 14(12), 1226; https://doi.org/10.3390/ph14121226 - 26 Nov 2021
Cited by 7 | Viewed by 2045
Abstract
We have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these [...] Read more.
We have previously reported in a feline model of acute peripheral vestibulopathy (APV) that the sudden, unilateral, and irreversible loss of vestibular inputs induces selective overexpression of small conductance calcium-activated potassium (SK) channels in the brain stem vestibular nuclei. Pharmacological blockade of these ion channels by the selective antagonist apamin significantly alleviated the evoked vestibular syndrome and accelerated vestibular compensation. In this follow-up study, we aimed at testing, using a behavioral approach, whether the antivertigo (AV) effect resulting from the antagonization of SK channels was species-dependent or whether it could be reproduced in a rodent APV model, whether other SK channel antagonists reproduced similar functional effects on the vestibular syndrome expression, and whether administration of SK agonist could also alter the vestibular syndrome. We also compared the AV effects of apamin and acetyl-DL-leucine, a reference AV compound used in human clinic. We demonstrate that the AV effect of apamin is also found in a rodent model of APV. Other SK antagonists also produce a trend of AV effect when administrated during the acute phase of the vertigo syndrome. Conversely, the vertigo syndrome is worsened upon administration of SK channel agonist. It is noteworthy that the AV effect of apamin is superior to that of acetyl-DL-leucine. Taken together, these data reinforce SK channels as a pharmacological target for modulating the manifestation of the vertigo syndrome during APV. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
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Review

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24 pages, 1152 KiB  
Review
Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 1: Modulation of TRPM4
by Zsigmond Máté Kovács, Csaba Dienes, Tamás Hézső, János Almássy, János Magyar, Tamás Bányász, Péter P. Nánási, Balázs Horváth and Norbert Szentandrássy
Pharmaceuticals 2022, 15(1), 81; https://doi.org/10.3390/ph15010081 - 10 Jan 2022
Cited by 4 | Viewed by 3370
Abstract
Transient receptor potential melastatin 4 is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+-sensitive and permeable to monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions [...] Read more.
Transient receptor potential melastatin 4 is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+-sensitive and permeable to monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions by regulating the membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the pharmacological modulation of TRPM4 by listing, comparing, and describing both endogenous and exogenous activators and inhibitors of the ion channel. Moreover, other strategies used to study TRPM4 functions are listed and described. These strategies include siRNA-mediated silencing of TRPM4, dominant-negative TRPM4 variants, and anti-TRPM4 antibodies. TRPM4 is receiving more and more attention and is likely to be the topic of research in the future. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
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34 pages, 616 KiB  
Review
Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 2: TRPM4 in Health and Disease
by Csaba Dienes, Zsigmond Máté Kovács, Tamás Hézső, János Almássy, János Magyar, Tamás Bányász, Péter P. Nánási, Balázs Horváth and Norbert Szentandrássy
Pharmaceuticals 2022, 15(1), 40; https://doi.org/10.3390/ph15010040 - 28 Dec 2021
Cited by 9 | Viewed by 3711
Abstract
Transient receptor potential melastatin 4 (TRPM4) is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+ sensitive and permeable for monovalent but not divalent cations. It is widely expressed in many organs and is involved in several [...] Read more.
Transient receptor potential melastatin 4 (TRPM4) is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+ sensitive and permeable for monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions; it regulates membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the currently available knowledge about the physiological and pathophysiological roles of TRPM4 in various tissues. These include the physiological functions of TRPM4 in the cells of the Langerhans islets of the pancreas, in various immune functions, in the regulation of vascular tone, in respiratory and other neuronal activities, in chemosensation, and in renal and cardiac physiology. TRPM4 contributes to pathological conditions such as overactive bladder, endothelial dysfunction, various types of malignant diseases and central nervous system conditions including stroke and injuries as well as in cardiac conditions such as arrhythmias, hypertrophy, and ischemia-reperfusion injuries. TRPM4 claims more and more attention and is likely to be the topic of research in the future. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
21 pages, 2645 KiB  
Review
Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation
by Jesús Borrego, Adam Feher, Norbert Jost, Gyorgy Panyi, Zoltan Varga and Ferenc Papp
Pharmaceuticals 2021, 14(12), 1303; https://doi.org/10.3390/ph14121303 - 14 Dec 2021
Cited by 10 | Viewed by 3816
Abstract
The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the [...] Read more.
The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
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27 pages, 2280 KiB  
Review
New Strategies for the Treatment of Atrial Fibrillation
by Norbert Jost, Torsten Christ and János Magyar
Pharmaceuticals 2021, 14(9), 926; https://doi.org/10.3390/ph14090926 - 15 Sep 2021
Cited by 7 | Viewed by 5262
Abstract
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the clinical practice. It significantly contributes to the morbidity and mortality of the elderly population. Over the past 25–30 years intense effort in basic research has advanced the understanding of the relationship between [...] Read more.
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the clinical practice. It significantly contributes to the morbidity and mortality of the elderly population. Over the past 25–30 years intense effort in basic research has advanced the understanding of the relationship between the pathophysiology of AF and atrial remodelling. Nowadays it is clear that the various forms of atrial remodelling (electrical, contractile and structural) play crucial role in initiating and maintaining the persistent and permanent types of AF. Unlike in ventricular fibrillation, in AF rapid ectopic firing originating from pulmonary veins and re-entry mechanism may induce and maintain (due to atrial remodelling) this complex cardiac arrhythmia. The present review presents and discusses in detail the latest knowledge on the role of remodelling in AF. Special attention is paid to novel concepts and pharmacological targets presumably relevant to the drug treatment of atrial fibrillation. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
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13 pages, 1097 KiB  
Review
Canine Myocytes Represent a Good Model for Human Ventricular Cells Regarding Their Electrophysiological Properties
by Péter P. Nánási, Balázs Horváth, Fábián Tar, János Almássy, Norbert Szentandrássy, Norbert Jost, István Baczkó, Tamás Bányász and András Varró
Pharmaceuticals 2021, 14(8), 748; https://doi.org/10.3390/ph14080748 - 29 Jul 2021
Cited by 13 | Viewed by 3633
Abstract
Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently [...] Read more.
Due to the limited availability of healthy human ventricular tissues, the most suitable animal model has to be applied for electrophysiological and pharmacological studies. This can be best identified by studying the properties of ion currents shaping the action potential in the frequently used laboratory animals, such as dogs, rabbits, guinea pigs, or rats, and comparing them to those of human cardiomyocytes. The authors of this article with the experience of three decades of electrophysiological studies, performed in mammalian and human ventricular tissues and isolated cardiomyocytes, summarize their results obtained regarding the major canine and human cardiac ion currents. Accordingly, L-type Ca2+ current (ICa), late Na+ current (INa-late), rapid and slow components of the delayed rectifier K+ current (IKr and IKs, respectively), inward rectifier K+ current (IK1), transient outward K+ current (Ito1), and Na+/Ca2+ exchange current (INCX) were characterized and compared. Importantly, many of these measurements were performed using the action potential voltage clamp technique allowing for visualization of the actual current profiles flowing during the ventricular action potential. Densities and shapes of these ion currents, as well as the action potential configuration, were similar in human and canine ventricular cells, except for the density of IK1 and the recovery kinetics of Ito. IK1 displayed a largely four-fold larger density in canine than human myocytes, and Ito recovery from inactivation displayed a somewhat different time course in the two species. On the basis of these results, it is concluded that canine ventricular cells represent a reasonably good model for human myocytes for electrophysiological studies, however, it must be borne in mind that due to their stronger IK1, the repolarization reserve is more pronounced in canine cells, and moderate differences in the frequency-dependent repolarization patterns can also be anticipated. Full article
(This article belongs to the Special Issue Ion Channels: Current Pharmacological Challenges)
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