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Article ; Online: Symmetrical Bispyridinium Compounds Act as Open Channel Blockers of Cation-Selective Ion Channels.

Haufe, Yves / Loser, Dominik / Danker, Timm / Nicke, Annette

ACS pharmacology & translational science

2024 Volume 7, Issue 3, Page(s) 771–786

Abstract: Current treatments against organophosphate poisoning (OPP) do not directly address effects mediated by the overstimulation of nicotinic acetylcholine receptors (nAChR). Non-oxime bispyridinium compounds (BPC) promote acetylcholine esterase-independent ... ...

Abstract	Current treatments against organophosphate poisoning (OPP) do not directly address effects mediated by the overstimulation of nicotinic acetylcholine receptors (nAChR). Non-oxime bispyridinium compounds (BPC) promote acetylcholine esterase-independent recovery of organophosphate-induced paralysis. Here, we test the hypothesis that they act by positive modulatory action on nAChRs. Using two-electrode voltage clamp analysis in combination with mutagenesis and molecular docking analysis, the potency and molecular mode of action of a series of nine BPCs was investigated on human α7 and muscle-type nAChRs expressed in
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ISSN	2575-9108
ISSN (online)	2575-9108
DOI	10.1021/acsptsci.3c00308
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Article ; Online: Laser-Induced Action Potential-Like Measurements of Cardiomyocytes on Microelectrode Arrays for Increased Predictivity of Safety Pharmacology.

Schaefer, Jasmin / Danker, Timm / Gebhardt, Karin / Kraushaar, Udo

Journal of visualized experiments : JoVE

2022 , Issue 187

Abstract: Life-threatening drug-induced cardiac arrhythmia is often preceded by prolonged cardiac action potentials (AP), commonly accompanied by small proarrhythmic membrane potential fluctuations. The shape and time course of the repolarizing fraction of the AP ... ...

Abstract	Life-threatening drug-induced cardiac arrhythmia is often preceded by prolonged cardiac action potentials (AP), commonly accompanied by small proarrhythmic membrane potential fluctuations. The shape and time course of the repolarizing fraction of the AP can be pivotal for the presence or absence of arrhythmia. Microelectrode arrays (MEA) allow easy access to cardiotoxic compound effects via extracellular field potentials (FP). Although a powerful and well-established tool in research and cardiac safety pharmacology, the FP waveform does not allow to infer the original AP shape due to the extracellular recording principle and the resulting intrinsic alternating current (AC) filtering. A novel device, described here, can repetitively open the membrane of cardiomyocytes cultivated on top of the MEA electrodes at multiple cultivation time points, using a highly focused nanosecond laser beam. The laser poration results in transforming the electrophysiological signal from FP to intracellular-like APs (laser-induced AP, liAP) and enables the recording of transcellular voltage deflections. This intracellular access allows a better description of the AP shape and a better and more sensitive classification of proarrhythmic potentials than regular MEA recordings. This system is a revolutionary extension to the existing electrophysiological methods, permitting accurate evaluation of cardiotoxic effect with all advantages of MEA-based recordings (easy, acute, and chronic experiments, signal propagation analysis, etc.).
MeSH term(s)	Action Potentials/physiology ; Arrhythmias, Cardiac ; Humans ; Lasers ; Microelectrodes ; Myocytes, Cardiac/physiology
Language	English
Publishing date	2022-09-13
Publishing country	United States
Document type	Journal Article ; Video-Audio Media ; Research Support, Non-U.S. Gov't
ZDB-ID	2259946-0
ISSN	1940-087X ; 1940-087X
ISSN (online)	1940-087X
ISSN	1940-087X
DOI	10.3791/64355
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Article: Toxicological and Safety Pharmacological Profiling of the Anti-Infective and Anti-Inflammatory Peptide Pep19-2.5.

Möller, Clemens / Heinbockel, Lena / Garidel, Patrick / Gutsmann, Thomas / Mauss, Karl / Weindl, Günther / Fukuoka, Satoshi / Loser, Dominik / Danker, Timm / Brandenburg, Klaus

Microorganisms

2022 Volume 10, Issue 12

Abstract: Aspidasept (Pep19-2.5) and its derivative Pep19-4LF ("Aspidasept II") are anti-infective and anti-inflammatory synthetic polypeptides currently in development for application against a variety of moderate to severe bacterial infections that could lead to ...

Abstract	Aspidasept (Pep19-2.5) and its derivative Pep19-4LF ("Aspidasept II") are anti-infective and anti-inflammatory synthetic polypeptides currently in development for application against a variety of moderate to severe bacterial infections that could lead to systemic inflammation, as in the case of severe sepsis and septic shock, as well as application to non-systemic diseases in the case of skin and soft tissue infections (SSTI). In the present study, Aspidasept and Aspidasept II and their part structures were analysed with respect to their toxic behavior in different established models against a variety of relevant cells, and in electrophysiological experiments targeting the hERG channel according to ICH S7B. Furthermore, the effects in mouse models of neurobiological behavior and the local lymph node according to OECD test guideline 429 were investigated, as well as a rat model of repeated dose toxicology according to ICH M3. The data provide conclusive information about potential toxic effects, thus specifying a therapeutic window for the application of the peptides. Therefore, these data allow us to define Aspidasept concentrations for their use in clinical studies as parenteral application.
Language	English
Publishing date	2022-12-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720891-6
ISSN	2076-2607
ISSN	2076-2607
DOI	10.3390/microorganisms10122412
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Article: Early identification of hERG liability in drug discovery programs by automated patch clamp.

Danker, Timm / Möller, Clemens

Frontiers in pharmacology

2014 Volume 5, Page(s) 203

Abstract: Blockade of the cardiac ion channel coded by human ether-à-gogo-related gene (hERG) can lead to cardiac arrhythmia, which has become a major concern in drug discovery and development. Automated electrophysiological patch clamp allows assessment of hERG ... ...

Abstract	Blockade of the cardiac ion channel coded by human ether-à-gogo-related gene (hERG) can lead to cardiac arrhythmia, which has become a major concern in drug discovery and development. Automated electrophysiological patch clamp allows assessment of hERG channel effects early in drug development to aid medicinal chemistry programs and has become routine in pharmaceutical companies. However, a number of potential sources of errors in setting up hERG channel assays by automated patch clamp can lead to misinterpretation of data or false effects being reported. This article describes protocols for automated electrophysiology screening of compound effects on the hERG channel current. Protocol details and the translation of criteria known from manual patch clamp experiments to automated patch clamp experiments to achieve good quality data are emphasized. Typical pitfalls and artifacts that may lead to misinterpretation of data are discussed. While this article focuses on hERG channel recordings using the QPatch (Sophion A/S, Copenhagen, Denmark) technology, many of the assay and protocol details given in this article can be transferred for setting up different ion channel assays by automated patch clamp and are similar on other planar patch clamp platforms.
Language	English
Publishing date	2014-09-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2014.00203
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Article ; Online: Functional evaluation of epilepsy-associated KCNT1 variants in multiple cellular systems reveals a predominant gain of function impact on channel properties.

Hinckley, Christopher A / Zhu, Zhonghua / Chu, Jen-Hwa / Gubbels, Cynthia / Danker, Timm / Cherry, Jonathan J / Whelan, Christopher D / Engle, Sandra J / Nguyen, Viet

Epilepsia

2023 Volume 64, Issue 8, Page(s) 2126–2136

Abstract: Objective: Gain of function variants in the sodium-activated potassium channel KCNT1 have been associated with pediatric epilepsy disorders. Here, we systematically examine a spectrum of KCNT1 variants and establish their impact on channel function in ... ...

Abstract	Objective: Gain of function variants in the sodium-activated potassium channel KCNT1 have been associated with pediatric epilepsy disorders. Here, we systematically examine a spectrum of KCNT1 variants and establish their impact on channel function in multiple cellular systems. Methods: KCNT1 variants identified from published reports and genetic screening of pediatric epilepsy patients were expressed in Xenopus oocytes and HEK cell lines. Variant impact on current magnitude, current-voltage relationships, and sodium ion modulation were examined. Results: We determined basic properties of KCNT1 in Xenopus oocyte and HEK systems, including the role of extra- and intracellular sodium in regulating KCNT1 activity. The most common six KCNT1 variants demonstrated strong gain of function (GOF) effects on one or more channel properties. Analysis of 36 total variants identified phenotypic heterogeneity but a strong tendency for pathogenic variants to exert GOF effects on channel properties. By controlling intracellular sodium, we demonstrate that multiple pathogenic KCNT1 variants modulate channel voltage dependence by altering the sensitivity to sodium ions. Significance: This study represents the largest systematic functional examination of KCNT1 variants to date. We both confirm previously reported GOF channel phenotypes and expand the number of variants with in vitro GOF effects. Our data provide further evidence that novel KCNT1 variants identified in epilepsy patients lead to disease through generalizable GOF mechanisms including increases in current magnitude and/or current-voltage relationships.
MeSH term(s)	Humans ; Potassium Channels, Sodium-Activated/genetics ; Gain of Function Mutation ; Mutation ; Epilepsy/genetics ; Potassium Channels/genetics ; Potassium Channels/metabolism ; Nerve Tissue Proteins/genetics
Chemical Substances	Potassium Channels, Sodium-Activated ; Potassium Channels ; KCNT1 protein, human ; Nerve Tissue Proteins
Language	English
Publishing date	2023-06-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/epi.17648
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Article ; Online: Catch and Patch: A Pipette-Based Approach for Automating Patch Clamp That Enables Cell Selection and Fast Compound Application.

Danker, Timm / Braun, Franziska / Silbernagl, Nikole / Guenther, Elke

Assay and drug development technologies

2016 Volume 14, Issue 2, Page(s) 144–155

Abstract: Manual patch clamp, the gold standard of electrophysiology, represents a powerful and versatile toolbox to stimulate, modulate, and record ion channel activity from membrane fragments and whole cells. The electrophysiological readout can be combined with ...

Abstract	Manual patch clamp, the gold standard of electrophysiology, represents a powerful and versatile toolbox to stimulate, modulate, and record ion channel activity from membrane fragments and whole cells. The electrophysiological readout can be combined with fluorescent or optogenetic methods and allows for ultrafast solution exchanges using specialized microfluidic tools. A hallmark of manual patch clamp is the intentional selection of individual cells for recording, often an essential prerequisite to generate meaningful data. So far, available automation solutions rely on random cell usage in the closed environment of a chip and thus sacrifice much of this versatility by design. To parallelize and automate the traditional patch clamp technique while perpetuating the full versatility of the method, we developed an approach to automation, which is based on active cell handling and targeted electrode placement rather than on random processes. This is achieved through an automated pipette positioning system, which guides the tips of recording pipettes with micrometer precision to a microfluidic cell handling device. Using a patch pipette array mounted on a conventional micromanipulator, our automated patch clamp process mimics the original manual patch clamp as closely as possible, yet achieving a configuration where recordings are obtained from many patch electrodes in parallel. In addition, our implementation is extensible by design to allow the easy integration of specialized equipment such as ultrafast compound application tools. The resulting system offers fully automated patch clamp on purposely selected cells and combines high-quality gigaseal recordings with solution switching in the millisecond timescale.
MeSH term(s)	Animals ; Automation ; CHO Cells ; Cell Separation/instrumentation ; Cells, Cultured ; Cricetulus ; Dose-Response Relationship, Drug ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels/metabolism ; Haloperidol/pharmacology ; Humans ; Patch-Clamp Techniques/instrumentation ; Quinidine/pharmacology ; Software ; Structure-Activity Relationship ; Time Factors ; Verapamil/pharmacology
Chemical Substances	Ether-A-Go-Go Potassium Channels ; Verapamil (CJ0O37KU29) ; Quinidine (ITX08688JL) ; Haloperidol (J6292F8L3D)
Language	English
Publishing date	2016-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Technical Report
ISSN	1557-8127
ISSN (online)	1557-8127
DOI	10.1089/adt.2015.696
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Article ; Online: Human neuronal signaling and communication assays to assess functional neurotoxicity.

Loser, Dominik / Schaefer, Jasmin / Danker, Timm / Möller, Clemens / Brüll, Markus / Suciu, Ilinca / Ückert, Anna-Katharina / Klima, Stefanie / Leist, Marcel / Kraushaar, Udo

Archives of toxicology

2020 Volume 95, Issue 1, Page(s) 229–252

Abstract: Prediction of drug toxicity on the human nervous system still relies mainly on animal experiments. Here, we developed an alternative system allowing assessment of complex signaling in both individual human neurons and on the network level. The LUHMES ... ...

Abstract	Prediction of drug toxicity on the human nervous system still relies mainly on animal experiments. Here, we developed an alternative system allowing assessment of complex signaling in both individual human neurons and on the network level. The LUHMES cultures used for our approach can be cultured in 384-well plates with high reproducibility. We established here high-throughput quantification of free intracellular Ca
MeSH term(s)	Action Potentials/drug effects ; Calcium/metabolism ; Calcium Signaling/drug effects ; Cells, Cultured ; Dopamine Plasma Membrane Transport Proteins/drug effects ; Dopamine Plasma Membrane Transport Proteins/metabolism ; High-Throughput Screening Assays ; Humans ; Nerve Net/drug effects ; Nerve Net/metabolism ; Nerve Net/pathology ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Neurotoxicity Syndromes/etiology ; Neurotoxicity Syndromes/metabolism ; Neurotoxicity Syndromes/pathology ; Patch-Clamp Techniques ; Receptors, Purinergic/drug effects ; Receptors, Purinergic/genetics ; Receptors, Purinergic/metabolism ; Time Factors ; Toxicity Tests ; Voltage-Gated Sodium Channels/drug effects ; Voltage-Gated Sodium Channels/metabolism
Chemical Substances	Dopamine Plasma Membrane Transport Proteins ; Receptors, Purinergic ; Voltage-Gated Sodium Channels ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2020-12-02
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-020-02956-3
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Article ; Online: Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons.

Loser, Dominik / Hinojosa, Maria G / Blum, Jonathan / Schaefer, Jasmin / Brüll, Markus / Johansson, Ylva / Suciu, Ilinca / Grillberger, Karin / Danker, Timm / Möller, Clemens / Gardner, Iain / Ecker, Gerhard F / Bennekou, Susanne H / Forsby, Anna / Kraushaar, Udo / Leist, Marcel

Archives of toxicology

2021 Volume 95, Issue 6, Page(s) 2081–2107

Abstract: Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human ... ...

Abstract	Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human neurons, and thus, affect the human adult or developing nervous system. We used SH-SY5Y neuroblastoma cells as established model of nicotinic acetylcholine receptor (nAChR) signaling. In parallel, we profiled dopaminergic neurons, generated from LUHMES neuronal precursor cells, as novel system to study nAChR activation in human post-mitotic neurons. Changes of the free intracellular Ca
MeSH term(s)	Calcium/metabolism ; Cell Line ; Cell Line, Tumor ; Dopaminergic Neurons/drug effects ; Dopaminergic Neurons/pathology ; Dose-Response Relationship, Drug ; Humans ; Neonicotinoids/administration & dosage ; Neonicotinoids/toxicity ; Neuroblastoma/metabolism ; Patch-Clamp Techniques ; Pesticides/toxicity ; Receptors, Nicotinic/drug effects ; Receptors, Nicotinic/metabolism ; Signal Transduction/drug effects
Chemical Substances	Neonicotinoids ; Pesticides ; Receptors, Nicotinic ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2021-03-29
Publishing country	Germany
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-021-03031-1
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Article ; Online: Acute effects of the imidacloprid metabolite desnitro-imidacloprid on human nACh receptors relevant for neuronal signaling.

Loser, Dominik / Grillberger, Karin / Hinojosa, Maria G / Blum, Jonathan / Haufe, Yves / Danker, Timm / Johansson, Ylva / Möller, Clemens / Nicke, Annette / Bennekou, Susanne H / Gardner, Iain / Bauch, Caroline / Walker, Paul / Forsby, Anna / Ecker, Gerhard F / Kraushaar, Udo / Leist, Marcel

Archives of toxicology

2021 Volume 95, Issue 12, Page(s) 3695–3716

Abstract: Several neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, ...

Abstract	Several neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, desnitro-imidacloprid (DN-IMI) is of special toxicological interest, as there is evidence (i) for human dietary exposure to this metabolite, (ii) and that DN-IMI is a strong trigger of mammalian nicotinic responses. We set out here to quantify responses of human nAChRs to DN-IMI and an alternative metabolite, IMI-olefin. To evaluate toxicological hazards, these data were then compared to those of IMI and nicotine. Ca
MeSH term(s)	Alkenes/chemistry ; Animals ; Cell Line ; Cell Line, Tumor ; Humans ; Imidazolines/pharmacology ; Molecular Docking Simulation ; Neonicotinoids/metabolism ; Neonicotinoids/pharmacology ; Neuroblastoma/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Nicotinic Agonists/pharmacology ; Nitro Compounds/metabolism ; Nitro Compounds/pharmacology ; Oocytes ; Pesticides/metabolism ; Pesticides/pharmacology ; Pyridines/pharmacology ; Receptors, Nicotinic/drug effects ; Receptors, Nicotinic/metabolism ; Signal Transduction/drug effects ; Xenopus laevis
Chemical Substances	Alkenes ; Imidazolines ; Neonicotinoids ; Nicotinic Agonists ; Nitro Compounds ; Pesticides ; Pyridines ; Receptors, Nicotinic ; desnitroimidacloprid ; imidacloprid (3BN7M937V8)
Language	English
Publishing date	2021-10-10
Publishing country	Germany
Document type	Comparative Study ; Journal Article
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-021-03168-z
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Book ; Thesis: Elektrophysiologische und Rasterkraftmikroskopische Untersuchungen an der Kernhülle

Danker, Timm

1999

Author's details	von Timm Danker
Language	German
Size	2 Mikrofiches, Ill., graph. Darst
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Univ., Diss.--Würzburg, 1999
Database	Former special subject collection: coastal and deep sea fishing

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