scholarly journals Molecular Pharmacology of K2P Potassium Channels

2021 ◽  
Vol 55 (S3) ◽  
pp. 87-107
Keyword(s):  
Potassium Channels ◽  
Binding Sites ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Drug Binding ◽  
Channel Blockers ◽  
Molecular Pharmacology ◽  
K2p Channel ◽  
Channel Inhibition ◽  
K2p Channels

Potassium channels of the tandem of two-pore-domain (K2P) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, after the initial cloning of the fifteen family members there was a lack of potent and/or selective modulators. By now a large variety of K2P channel modulators (activators and blockers) have been described, especially for TASK-1, TASK-3, TREK-1, TREK2, TRAAK and TRESK channels. Recently obtained crystal structures of K2P channels, alanine scanning approaches to map drug binding sites, in silico experiments with molecular dynamics simulations (MDs) combined with electrophysiological studies to reveal the mechanism of channel inhibition/activation, yielded a good understanding of the molecular pharmacology of these channels. Besides summarizing drugs that were identified to modulate K2P channels, the main focus of this article is on describing the differential binding sites and mechanisms of channel modulation that are utilized by the different K2P channel blockers and activators.

scholarly journals The molecular basis for an allosteric inhibition of K+-flux gating in K2P channels

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Susanne Rinné ◽  
Aytug K Kiper ◽  
Kirsty S Vowinkel ◽  
David Ramírez ◽  
Marcus Schewe ◽  
...  
Keyword(s):  
Binding Site ◽  
Drug Targets ◽  
Drug Binding ◽  
Inhibition Mechanism ◽  
Central Cavity ◽  
Allosteric Inhibition ◽  
Mechanism Of Inhibition ◽  
Gating Mechanism ◽  
Channel Inhibition ◽  
K2p Channels

Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medical need to identify novel drug-binding sites outside the conserved lipophilic central cavity and to identify new allosteric mechanisms of channel inhibition. Here, we identified a novel binding site and allosteric inhibition mechanism, disrupting the recently proposed K+-flux gating mechanism of K2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The new binding site and allosteric mechanism of inhibition provide structural and mechanistic insights into the gating of TASK channels and the basis for the drug design of a new class of potent blockers targeting specific types of K2P channels.

scholarly journals Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?

2017 ◽  
Vol 95 (11) ◽  
pp. 1313-1318 ◽  
Author(s):  
Ursula Ravens
Keyword(s):  
Atrial Fibrillation ◽  
Drug Targets ◽  
Antiarrhythmic Drugs ◽  
Drug Effects ◽  
K Channel ◽  
Channel Blockers ◽  
Electrophysiological Properties ◽  
Cardiac Functions ◽  
K2p Channels ◽  
Pore Domain

In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K+) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two-pore domain K+ (K2P) channels (tandem of P domains, weak inward-rectifying K+ channels (TWIK-1), TWIK-related acid-sensitive K+ channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents ITWIK-1, ITASK-1, and ITASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.

Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond

2021 ◽  
Vol 61 (1) ◽  
pp. 401-420 ◽  
Author(s):  
Alistair Mathie ◽  
Emma L. Veale ◽  
Kevin P. Cunningham ◽  
Robyn G. Holden ◽  
Paul D. Wright
Keyword(s):  
Small Molecule ◽  
Drug Targets ◽  
Cell Activity ◽  
Therapeutic Benefit ◽  
Resting Membrane Potential ◽  
Screening Programs ◽  
K2p Channel ◽  
K2p Channels ◽  
Pharmacological Regulation ◽  
Pore Domain

Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.

scholarly journals Case study: Paralog diverged features may help reduce off-target effects of drugs

2016 ◽  
Author(s):  
Zhining Sa ◽  
Jingqi Zhou ◽  
Yangyun Zou ◽  
Xun Gu
Keyword(s):  
Side Effects ◽  
Physicochemical Properties ◽  
Binding Sites ◽  
Drug Targets ◽  
Functional Divergence ◽  
Drug Binding ◽  
Type Ii ◽  
Glucagon Receptor ◽  
Protein Receptors ◽  
Glucagon Like Peptide 1

AbstractSide effects from targeted drugs is a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and exhibit similar structures and drug-binding pockets. In this study, we analyzed amino acid residues with type-II functional divergence, i.e., sites that are conserved in sequence constraints but differ in physicochemical properties between paralogs, to identify targetable differences between two paralogs. We analyzed paralogous protein receptors in the glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), which are clinically validated drug targets in patients with type 2 diabetes and exhibit divergence in ligands, showing opposing roles in regulating glucose homeostasis. We identified 8 residues related to type-II functional divergence, which are conserved in functional constraints but differ in physicochemical properties between GCGR and GLP-1R. We detected significant enrichment of predicted residues in binding sites of the antagonist MK-0893 to GCGR. We also identified a type-II functional divergence-related residue involved in ligand-specific effects that was critical for agonist-mediated activation of GLP-1R. We describe the important role of type-II functional divergence-related sites in paralog discrimination, enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.

scholarly journals Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2914
Author(s):  
Felix Wiedmann ◽  
Norbert Frey ◽  
Constanze Schmidt
Keyword(s):  
Action Potential ◽  
Cardiac Fibrosis ◽  
Cardiac Tissue ◽  
Therapeutic Potential ◽  
Expression Patterns ◽  
Cell Types ◽  
Resting Membrane Potential ◽  
K2p Channel ◽  
K2p Channels ◽  
Pore Domain

Two-pore-domain potassium (K2P-) channels conduct outward K+ currents that maintain the resting membrane potential and modulate action potential repolarization. Members of the K2P channel family are widely expressed among different human cell types and organs where they were shown to regulate important physiological processes. Their functional activity is controlled by a broad variety of different stimuli, like pH level, temperature, and mechanical stress but also by the presence of lipids or pharmacological agents. In patients suffering from cardiovascular diseases, alterations in K2P-channel expression and function have been observed, suggesting functional significance and a potential therapeutic role of these ion channels. For example, upregulation of atrial specific K2P3.1 (TASK-1) currents in atrial fibrillation (AF) patients was shown to contribute to atrial action potential duration shortening, a key feature of AF-associated atrial electrical remodelling. Therefore, targeting K2P3.1 (TASK-1) channels might constitute an intriguing strategy for AF treatment. Further, mechanoactive K2P2.1 (TREK-1) currents have been implicated in the development of cardiac hypertrophy, cardiac fibrosis and heart failure. Cardiovascular expression of other K2P channels has been described, functional evidence in cardiac tissue however remains sparse. In the present review, expression, function, and regulation of cardiovascular K2P channels are summarized and compared among different species. Remodelling patterns, observed in disease models are discussed and compared to findings from clinical patients to assess the therapeutic potential of K2P channels.

scholarly journals LiP-Quant, an automated chemoproteomic approach to identify drug targets in complex proteomes

2019 ◽  
Author(s):  
Ilaria Piazza ◽  
Nigel Beaton ◽  
Roland Bruderer ◽  
Thomas Knobloch ◽  
Crystel Barbisan ◽  
...  
Keyword(s):  
Small Molecule ◽  
Binding Sites ◽  
Drug Target ◽  
Drug Targets ◽  
Target Identification ◽  
Limited Proteolysis ◽  
Drug Binding ◽  
Homologous Proteins ◽  
Protein Targets ◽  
Drug Target Identification

Chemoproteomics is a key technology to characterize the mode of action of drugs, as it directly identifies the protein targets of bioactive compounds and aids in developing optimized small-molecule compounds. Current unbiased approaches cannot directly pinpoint the interaction surfaces between ligands and protein targets. To address his limitation we have developed a new drug target deconvolution approach based on limited proteolysis coupled with mass spectrometry that works across species including human cells (LiP-Quant). LiP-Quant features an automated data analysis pipeline and peptide-level resolution for the identification of any small-molecule binding sites, Here we demonstrate drug target identification by LiP-Quant across compound classes, including compounds targeting kinases and phosphatases. We demonstrate that LiP-Quant estimates the half maximal effective concentration (EC50) of compound binding sites in whole cell lysates. LiP-Quant identifies targets of both selective and promiscuous drugs and correctly discriminates drug binding to homologous proteins. We finally show that the LiP-Quant technology identifies targets of a novel research compound of biotechnological interest.

scholarly journals Development of IKATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant KIR6.2 Based Channels for Treating DEND Syndrome

2022 ◽  
Vol 12 ◽  
Author(s):  
Marien J. C. Houtman ◽  
Theres Friesacher ◽  
Xingyu Chen ◽  
Eva-Maria Zangerl-Plessl ◽  
Marcel A. G. van der Heyden ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Patch Clamp ◽  
Molecular Dynamics Simulations ◽  
Drug Binding ◽  
Channel Blockers ◽  
Drug Candidates ◽  
Channel Inhibition ◽  
Patch Clamp Electrophysiology ◽  
Dynamics Simulations ◽  
Inside Out

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels.Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships.Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27–37 μM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 μM) and Q52R (IC50 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2–3 μM), while Q52R inhibition was 15–20% at 10 μM.Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity.

scholarly journals DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions

2021 ◽  
Author(s):  
Anirban Ghosh ◽  
Eric Largy ◽  
Valérie Gabelica
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Drug Binding ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Nmr Structures ◽  
G Quadruplex ◽  
Screening Assays

Abstract G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually ∼100 mM) potassium, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM trimethylammonium acetate. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in the g4dbr package (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).

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