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Pharmaceuticals
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Potassium Channels as Novel Therapeutic Targets
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Potassium Channels as Novel Therapeutic Targets

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

Deadline for manuscript submissions: 30 August 2024 | Viewed by 10979

Special Issue Editors

Dr. Eva-Maria Zangerl-Plessl

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences , Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
Interests: inward rectifying potassium channels; hERG channel; molecular dynamics simulations
Dr. Anna Stary-Weinzinger

E-Mail Website
Guest Editor
Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
Interests: ion channel pharmacology; molecular modelling; molecular dynamics simulations; drug repurposing for rare ion channel diseases

Special Issue Information

Dear Colleagues,

We would like to promote the upcoming Special Issue of Pharmaceuticals titled “Potassium Channels as Novel Therapeutic Targets”. K+ channels constitute the largest and most diverse family of ion channels, with almost 80 different genes encoding the principal pore-forming subunits. They are found in nearly all cell types, and play a critical role in diverse physiological functions such as the repolarization of neuronal and cardiac action potentials, maintaining vascular tone, and the regulation of the secretion of hormones. Recent progress in structural biology, molecular pharmacology, and electrophysiology/in vivo experiments led to a good understanding of the physiological role of many K+ channel members and their therapeutic potential. Pharmacological strategies for targeting these channels include venom peptides, antibodies, and small molecules. Modulation can occur in the form of blockers that inhibit the channels or in the form of openers that activate these channels. With their often tissue-defined distribution, they offer tremendous opportunities for the development of new drugs to treat, for example, cardiovascular disorders, neurological diseases, cancer, as well as autoimmune and metabolic diseases. Still, few selective K+ channel activators or inhibitors are currently licensed for clinical use. Challenges in the field of ion channel modulation include a lack of selectivity of the drugs for the target channel, due to the close relatedness of subfamily members. A special case constitutes the human ether-a-go-go-related gene (hERG) channel, which is responsible for many adverse drug actions and remains a major impediment for drug development.

In this Special Issue, we aim to bring together research from experts in the field that highlight therapeutic agents and strategies, and which identify future directions that will lead to novel discoveries and therapies for K+-channel-associated diseases.

Dr. Eva-Maria Zangerl-Plessl
Dr. Anna Stary-Weinzinger
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

  • potassium channels
  • drug modulation
  • channelopathy
  • drug development
  • cardiac
  • neuronal
  • vascular
  • activators
  • inhibitors
  • off-target pharmacology

Published Papers (5 papers)

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Research

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20 pages, 5053 KiB  
Article
Inhibition of the hERG Potassium Channel by a Methanesulphonate-Free E-4031 Analogue
by Matthew V. Helliwell, Yihong Zhang, Aziza El Harchi, Christopher E. Dempsey and Jules C. Hancox
Pharmaceuticals 2023, 16(9), 1204; https://doi.org/10.3390/ph16091204 - 24 Aug 2023
Cited by 1 | Viewed by 1202
Abstract
hERG (human Ether-à-go-go Related Gene)-encoded potassium channels underlie the cardiac rapid delayed rectifier (IKr) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is [...] Read more.
hERG (human Ether-à-go-go Related Gene)-encoded potassium channels underlie the cardiac rapid delayed rectifier (IKr) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is a high potency hERG channel inhibitor from the methanesulphonanilide drug family. This study utilized a methanesulphonate-lacking E-4031 analogue, “E-4031-17”, to evaluate the role of the methanesulphonamide group in E-4031 inhibition of hERG. Whole-cell patch-clamp measurements of the hERG current (IhERG) were made at physiological temperature from HEK 293 cells expressing wild-type (WT) and mutant hERG constructs. For E-4031, WT IhERG was inhibited by a half-maximal inhibitory concentration (IC50) of 15.8 nM, whilst the comparable value for E-4031-17 was 40.3 nM. Both compounds exhibited voltage- and time-dependent inhibition, but they differed in their response to successive applications of a long (10 s) depolarisation protocol, consistent with greater dissociation of E-4031-17 than the parent compound between applied commands. Voltage-dependent inactivation was left-ward voltage shifted for E-4031 but not for E-4031-17; however, inhibition by both compounds was strongly reduced by attenuated-inactivation mutations. Mutations of S6 and S5 aromatic residues (F656V, Y652A, F557L) greatly attenuated actions of both drugs. The S624A mutation also reduced IhERG inhibition by both molecules. Overall, these results demonstrate that the lack of a methanesulphonate in E-4031-17 is not an impediment to high potency inhibition of IhERG. Full article
(This article belongs to the Special Issue Potassium Channels as Novel Therapeutic Targets)
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13 pages, 10271 KiB  
Article
Neuroprotection in an Experimental Model of Multiple Sclerosis via Opening of Big Conductance, Calcium-Activated Potassium Channels
by Gareth Pryce, Sofia Sisay, Gavin Giovannoni, David L. Selwood and David Baker
Pharmaceuticals 2023, 16(7), 972; https://doi.org/10.3390/ph16070972 - 07 Jul 2023
Viewed by 1587
Abstract
Big conductance calcium-activated (BK) channel openers can inhibit pathologically driven neural hyperactivity to control symptoms via hyperpolarizing signals to limit neural excitability. We hypothesized that BK channel openers would be neuroprotective during neuroinflammatory, autoimmune disease. The neurodegenerative disease was induced in a mouse [...] Read more.
Big conductance calcium-activated (BK) channel openers can inhibit pathologically driven neural hyperactivity to control symptoms via hyperpolarizing signals to limit neural excitability. We hypothesized that BK channel openers would be neuroprotective during neuroinflammatory, autoimmune disease. The neurodegenerative disease was induced in a mouse experimental autoimmune encephalomyelitis model with translational value to detect neuroprotection in multiple sclerosis. Following the treatment with the BK channel openers, BMS-204253 and VSN16R, neuroprotection was assessed using subjective and objective clinical outcomes and by quantitating spinal nerve content. Treatment with BMS-204253 and VSN16R did not inhibit the development of relapsing autoimmunity, consistent with minimal channel expression via immune cells, nor did it change leukocyte levels in rodents or humans. However, it inhibited the accumulation of nerve loss and disability as a consequence of autoimmunity. Therefore, in addition to symptom control, BK channel openers have the potential to save nerves from excitotoxic damage and could be useful as either stand-alone neuroprotective agents or as add-ons to current disease-modifying treatments that block relapsing MS but do not have any direct neuroprotective activity. Full article
(This article belongs to the Special Issue Potassium Channels as Novel Therapeutic Targets)
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18 pages, 5788 KiB  
Article
Chronic Propafenone Application Increases Functional KIR2.1 Expression In Vitro
by Encan Li, Willy Kool, Liset Woolschot and Marcel A. G. van der Heyden
Pharmaceuticals 2023, 16(3), 404; https://doi.org/10.3390/ph16030404 - 07 Mar 2023
Cited by 1 | Viewed by 1616
Abstract
Expression and activity of inwardly rectifying potassium (KIR) channels within the heart are strictly regulated. KIR channels have an important role in shaping cardiac action potentials, having a limited conductance at depolarized potentials but contributing to the final stage of [...] Read more.
Expression and activity of inwardly rectifying potassium (KIR) channels within the heart are strictly regulated. KIR channels have an important role in shaping cardiac action potentials, having a limited conductance at depolarized potentials but contributing to the final stage of repolarization and resting membrane stability. Impaired KIR2.1 function causes Andersen-Tawil Syndrome (ATS) and is associated with heart failure. Restoring KIR2.1 function by agonists of KIR2.1 (AgoKirs) would be beneficial. The class 1c antiarrhythmic drug propafenone is identified as an AgoKir; however, its long-term effects on KIR2.1 protein expression, subcellular localization, and function are unknown. Propafenone’s long-term effect on KIR2.1 expression and its underlying mechanisms in vitro were investigated. KIR2.1-carried currents were measured by single-cell patch-clamp electrophysiology. KIR2.1 protein expression levels were determined by Western blot analysis, whereas conventional immunofluorescence and advanced live-imaging microscopy were used to assess the subcellular localization of KIR2.1 proteins. Acute propafenone treatment at low concentrations supports the ability of propafenone to function as an AgoKir without disturbing KIR2.1 protein handling. Chronic propafenone treatment (at 25–100 times higher concentrations than in the acute treatment) increases KIR2.1 protein expression and KIR2.1 current densities in vitro, which are potentially associated with pre-lysosomal trafficking inhibition. Full article
(This article belongs to the Special Issue Potassium Channels as Novel Therapeutic Targets)
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12 pages, 3950 KiB  
Article
Pharmacological Profiling of KATP Channel Modulators: An Outlook for New Treatment Opportunities for Migraine
by Tino Dyhring, Inger Jansen-Olesen, Palle Christophersen and Jes Olesen
Pharmaceuticals 2023, 16(2), 225; https://doi.org/10.3390/ph16020225 - 01 Feb 2023
Cited by 3 | Viewed by 1768
Abstract
Migraine is a highly disabling pain disorder with huge socioeconomic and personal costs. It is genetically heterogenous leading to variability in response to current treatments and frequent lack of response. Thus, new treatment strategies are needed. A combination of preclinical and clinical data [...] Read more.
Migraine is a highly disabling pain disorder with huge socioeconomic and personal costs. It is genetically heterogenous leading to variability in response to current treatments and frequent lack of response. Thus, new treatment strategies are needed. A combination of preclinical and clinical data indicate that ATP-sensitive potassium (KATP) channel inhibitors could be novel and highly effective drugs in the treatment of migraine. The subtype Kir6.1/SUR2B is of particular interest and inhibitors specific for this cranio-vascular KATP channel subtype may qualify as future migraine drugs. Historically, different technologies and methods have been undertaken to characterize KATP channel modulators and, therefore, a head-to-head comparison of potency and selectivity between the different KATP subtypes is difficult to assess. Here, we characterize available KATP channel activators and inhibitors in fluorescence-based thallium-flux assays using HEK293 cells stably expressing human Kir6.1/SUR2B, Kir6.2/SUR1, and Kir6.2/SUR2A KATP channels. Among the openers tested, levcromakalim, Y-26763, pinacidil, P-1075, ZM226600, ZD0947, and A-278637 showed preference for the KATP channel subtype Kir6.1/SUR2B, whereas BMS-191095, NN414, and VU0071306 demonstrated preferred activation of the Kir6.2/SUR1 subtype. In the group of KATP channel blockers, only Rosiglitazone and PNU-37783A showed selective inhibition of the Kir6.1/SUR2B subtype. PNU-37783A was stopped in clinical development and Rosiglitazone has a low potency for the vascular KATP channel subtype. Therefore, development of novel selective KATP channel blockers, having a benign side effect profile, are needed to clinically prove inhibition of Kir6.1/SUR2B as an effective migraine treatment. Full article
(This article belongs to the Special Issue Potassium Channels as Novel Therapeutic Targets)
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18 pages, 3598 KiB  
Review
Involvement of Potassium Channel Signalling in Migraine Pathophysiology
by Mohammad Al-Mahdi Al-Karagholi
Pharmaceuticals 2023, 16(3), 438; https://doi.org/10.3390/ph16030438 - 14 Mar 2023
Cited by 5 | Viewed by 4052
Abstract
Migraine is a primary headache disorder ranked as the leading cause of years lived with disability among individuals younger than 50 years. The aetiology of migraine is complex and might involve several molecules of different signalling pathways. Emerging evidence implicates potassium channels, predominantly [...] Read more.
Migraine is a primary headache disorder ranked as the leading cause of years lived with disability among individuals younger than 50 years. The aetiology of migraine is complex and might involve several molecules of different signalling pathways. Emerging evidence implicates potassium channels, predominantly ATP-sensitive potassium (KATP) channels and large (big) calcium-sensitive potassium (BKCa) channels in migraine attack initiation. Basic neuroscience revealed that stimulation of potassium channels activated and sensitized trigeminovascular neurons. Clinical trials showed that administration of potassium channel openers caused headache and migraine attack associated with dilation of cephalic arteries. The present review highlights the molecular structure and physiological function of KATP and BKCa channels, presents recent insights into the role of potassium channels in migraine pathophysiology, and discusses possible complementary effects and interdependence of potassium channels in migraine attack initiation. Full article
(This article belongs to the Special Issue Potassium Channels as Novel Therapeutic Targets)
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