A5102763774- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- Ion Transport and Channel Regulation
- Membrane-based Ion Separation Techniques
- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Lipid Membrane Structure and Behavior
- Ion Channels and Receptors
- Computational Drug Discovery Methods
- Nicotinic Acetylcholine Receptors Study
- Advanced biosensing and bioanalysis techniques
- Erythrocyte Function and Pathophysiology
- Cardiac Arrhythmias and Treatments
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- Adipose Tissue and Metabolism
- Pharmacological Receptor Mechanisms and Effects
- Neurological disorders and treatments
- Cellular transport and secretion
- MicroRNA in disease regulation
- Atrial Fibrillation Management and Outcomes
- Coordination Chemistry and Organometallics
- interferon and immune responses
- Hormonal Regulation and Hypertension
- Semiconductor materials and devices
Philipps University of Marburg
2007-2025
Justus-Liebig-Universität Gießen
2019
Brain (Germany)
2019
Czech Academy of Sciences, Institute of Physiology
2018
University of Utah
2007
A key to potassium channel activation Using drugs activate channels has the potential treat conditions like epilepsy, heart arrhythmias, and pain. Schewe et al. report a class of negatively charged activators (NCAs) with defined pharmacore that use similar mechanism many types channels. X-ray crystallography, functional analysis, molecular dynamics simulations showed NCAs bind below selectivity filter open gate Targeting this NCA site might be exploited in rational drug design. Science , issue p. 875
Research Article27 February 2017Open Access Transparent process Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia Niels Decher Corresponding Author [email protected] orcid.org/0000-0001-8892-1231 Institute of Physiology Pathophysiology, Vegetative Physiology, Philipps-University Marburg, Germany Search for more papers by this author Beatriz Ortiz-Bonnin Corinna Friedrich Department Cardiovascular Medicine, Genetics Heart Diseases (IfGH), University Hospital...
Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides regulating plasma membrane excitability, SK activation provides neuroprotection against ferroptotic cell death by reducing mitochondrial Ca2+ uptake and reactive oxygen species (ROS). In this study, we employed multifaceted approach, integrating structure-based computational techniques, strategically design synthesize an innovative...
Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as NaV1.5, KV1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed multi-target inhibitors these to address AF. Compound 6f emerged most potent in series, demonstrating a strong inhibition (IC50 ∼0.3 μM), moderate NaV1.5 ∼21.2 μM) subtle KV1.5 ∼81.5 alongside unexpected activation TASK-4 (∼40% at 100 μM). Functional assays on human atrial cardiomyocytes...
The endosomal SNARE protein syntaxin-8 interacts with the acid-sensitive potassium channel TASK-1. functional relevance of this interaction was studied by heterologous expression these proteins (and mutants thereof) in Xenopus oocytes and mammalian cell lines. Coexpression caused a fourfold reduction TASK-1 current, corresponding at surface, marked increase rate endocytosis channel. colocalized early compartment, as indicated markers 2xFYVE rab5. stimulatory effect on abolished when both an...
Two-pore-domain potassium (K2P) channels are key regulators of many physiological and pathophysiological processes thus emerged as promising drug targets. As for other channels, there is a lack selective blockers, since drugs preferentially bind to conserved binding site located in the central cavity. Thus, high medical need identify novel drug-binding sites outside lipophilic cavity new allosteric mechanisms channel inhibition. Here, we identified inhibition mechanism, disrupting recently...
Andersen syndrome (AS) is a rare genetic disease caused by mutations of the potassium channel Kir2.1 (KCNJ2). We identified two unrelated patients with in slide helix leading to AS. The functional consequences these mutations, Y68D and D78Y, were studied compared previously reported mutations.Channel function surface expression voltage clamp recordings chemiluminescence assay Xenopus laevis oocytes patch fluorescence microscopy HEK293 cells. In addition, phosphatidylinositol bisphosphate...
A1899 is a potent and selective inhibitor of the two-pore domain potassium (K2P) channel TASK-1. It was previously reported that acts as an open-channel blocker binds to residues P1 P2 regions, M2 M4 segments, halothane response element. The recently described crystal structures K2P channels together with newly identified side fenestrations indicate relevant for TASK-1 inhibition are not purely facing central cavity initially proposed. Accordingly, binding site mechanism might need...
Abstract Two-pore-domain potassium (K 2P ) channels have a large extracellular cap structure formed by two M1-P1 linkers, containing cysteine for dimerization. However, this is not present in the TASK-1/3/5 subfamily. The functional role of poorly understood and it remained unclear whether K assemble domain-swapped orientation or not. Functional alanine-mutagenesis screens TASK-1 TRAAK were used to build an silico model cap. According our data disulfide-bridge free TASK similar that other...
TASK-3 is a two-pore domain potassium (K2P) channel highly expressed in the hippocampus, cerebellum, and cortex. has been identified as an oncogenic it overexpressed different cancer types. For this reason, development of new blockers could influence pharmacological treatment several neurological conditions. In present work, we searched for novel by using virtual screening protocol that includes pharmacophore modeling, molecular docking, free energy calculations. With protocol, 19 potential...
TASK-3 potassium (K+) channels are highly expressed in the central nervous system, regulating membrane potential of excitable cells. is involved neurotransmitter action and has been identified as an oncogenic K+ channel. For this reason, understanding mechanism pharmacological modulators these essential to obtain new therapeutic strategies. In study we describe binding mode potent antagonist PK-THPP into blocks TASK-1, closest relative channel TASK-3, with almost nine-times less potency. Our...
The ascending brainstem transmitter acetylcholine depolarizes thalamocortical relay neurons while it induces hyperpolarization in local circuit inhibitory interneurons. Sustained K+ currents are modulated thalamic to control their activity modes; for the interneurons molecular nature of underlying ion channels is as yet unknown. Activation TASK-1 results and suppression action potential firing. modulation cascade involves a non-receptor tyrosine kinase, c-Src. present study identifies novel...
Background and Purpose: Parkinson’s disease (PD) is clinically defined by the presence of cardinal motor symptoms, which are associated with a loss dopaminergic nigrostriatal neurons in substantia nigra pars compacta (SNpc). While SNpc serve as prototypical cell-type to study cellular vulnerability PD, there an unmet need extent our efforts other at risk. The noradrenergic locus coeruleus (LC) represents one first brain structures affected plays not only crucial role for evolving non-motor...
TASK channels are unusual members of the two-pore domain potassium (K 2P ) channel family, with unique and unexplained physiological pharmacological characteristics. TASKs found in neurons 1,2 , cardiomyocytes 3–5 vascular smooth muscle cells 6 where they involved regulation heart rate 7 pulmonary artery tone 6,8 sleep/wake cycles 9 responses to volatile anaesthetics 9–12 . K regulate resting membrane potential, providing background + currents controlled by numerous stimuli 13,14 Unlike...
Two-pore domain potassium (K2P) channels maintain the cell's background conductance by stabilizing resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. K2P were crystallized "up" and "down" states. The movements of pore-lining TM4 helix produce aperture or closure side fenestrations that connect lipid with central cavity. When is up-state, are closed, while they open down-state. It thought fenestration states related to activity opening...
TASK channels belong to the two-pore-domain potassium (K2P) channel family. TASK-1 is discussed contribute chronic atrial fibrillation (AFib) and has been together with uncoupling protein 1 found as a marker of brown adipose tissue (BAT) fat. In addition, was linked in genome-wide association study an increased body mass index. A recent showed that inhibition causing obesity mice by BAT whitening these effects are mineralocorticoid receptor pathway, albeit mechanism remained elusive....
Popeye domain containing (POPDC) proteins are predominantly expressed in the heart and skeletal muscle, modulating K
Potassium channel mutations play an important role in neurological diseases, such as spinocerebellar ataxia (SCA). SCA is a heterogeneous autosomal-dominant neurodegenerative disorder with multiple sub-entities, SCA13, which characterized by the voltage-gated potassium Kv3.3 ( KCNC3 ). In this study, we present rare and atypical case of SCA13 predominant episodic central rotational vertigo, while patient suffered only from mild progressive cerebellar symptoms, dysarthria, gait stand,...