المؤلفون: DOMBOVSKI, Alexander, STEIGERWALD, Ruben, RITTER, Nadine, DISSE, Paul, GOERGES, Gunnar, OSTHUES, Jana, AYMANNS, Isabel, DILKAUTE, Carina, SCHREIBER, Julian, DÜFER, Martina, SEEBOHM, Guiscard, WÜNSCH, Bernhard, JOSE, Joachim

المساهمون: DFG

المصدر: Journal of Pharmaceutical Analysis ; ISSN 2095-1779

مصطلحات موضوعية: Analytical Chemistry, Electrochemistry, Spectroscopy, Drug Discovery, Pharmaceutical Science, Pharmacy

الإتاحة: https://doi.org/10.1016/j.jpha.2024.01.013Test
https://api.elsevier.com/content/article/PII:S2095177924000327?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2095177924000327?httpAccept=text/plainTest

المؤلفون: Ritter, Nadine, Disse, Paul, Aymanns, Isabel, Mücher, Lena, Schreiber, Julian A., Brenker, Christoph, Strünker, Timo, Schepmann, Dirk, Budde, Thomas, Strutz-Seebohm, Nathalie, Ametamey, Simon M., Wünsch, Bernhard, Seebohm, Guiscard

المصدر: Molecular Neurobiology, 60 (12)

مصطلحات موضوعية: iGluRs, GluN2B, Ifenprodil, Alternative splicing, 3-Benzazepine

الوصف: N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications. Here, we identified (R)-OF-NB1 as a promising splice variant selective NMDAR antagonist. We investigated the interaction of (R)-OF-NB1 and NMDAR from a biochemical, bioinformatical, and electrophysiological perspective to characterize the downstream allosteric modulation of NMDAR by 3-benzazepine derivatives. The allosteric modulatory pathway starts at the ifenprodil binding pocket in the amino terminal domain and immobilizes the connecting & alpha;5-helix to the ligand binding domain, resulting in inhibition. In contrast, the exon 5 splice variant GluN1-1b elevates the NMDARs flexibility and promotes the open state of its ligand binding domain. ; ISSN:0893-7648 ; ISSN:1559-1182

وصف الملف: application/application/pdf

العلاقة: info:eu-repo/semantics/altIdentifier/wos/001043360500004; http://hdl.handle.net/20.500.11850/628132Test

الإتاحة: https://doi.org/20.500.11850/628132Test
https://doi.org/10.3929/ethz-b-000628132Test
https://doi.org/10.1007/s12035-023-03526-1Test
https://hdl.handle.net/20.500.11850/628132Test

المؤلفون: Marx, Nico, Disse, Paul, Aymanns, Isabel, Seebohm, Guiscard, Busch, Karin B.

المصدر: Biochimica et Biophysica Acta (BBA) - Bioenergetics ; volume 1863, page 148799 ; ISSN 0005-2728

مصطلحات موضوعية: Cell Biology, Biochemistry, Biophysics

الإتاحة: https://doi.org/10.1016/j.bbabio.2022.148799Test
https://api.elsevier.com/content/article/PII:S0005272822002699?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0005272822002699?httpAccept=text/plainTest

المؤلفون: Disse, Paul¹ (AUTHOR), Aymanns, Isabel¹ (AUTHOR), Mücher, Lena¹ (AUTHOR), Sandmann, Sarah² (AUTHOR), Varghese, Julian² (AUTHOR), Ritter, Nadine¹ (AUTHOR), Strutz-Seebohm, Nathalie¹ (AUTHOR), Seebohm, Guiscard¹ (AUTHOR) guiscard.seebohm@ukmuenster.de, Peischard, Stefan¹ (AUTHOR) guiscard.seebohm@ukmuenster.de

المصدر: International Journal of Molecular Sciences. Sep2023, Vol. 24 Issue 17, p13366. 17p.

مصطلحات موضوعية: *HEART cells, *HEART conduction system, *EXTRACELLULAR matrix, *CELLULAR signal transduction, *PURKINJE cells, *TISSUE engineering, *CARDIAC contraction

مستخلص: The human heart controls blood flow, and therewith enables the adequate supply of oxygen and nutrients to the body. The correct function of the heart is coordinated by the interplay of different cardiac cell types. Thereby, one can distinguish between cells of the working myocardium, the pace-making cells in the sinoatrial node (SAN) and the conduction system cells in the AV-node, the His-bundle or the Purkinje fibres. Tissue-engineering approaches aim to generate hiPSC-derived cardiac tissues for disease modelling and therapeutic usage with a significant improvement in the differentiation quality of myocardium and pace-making cells. The differentiation of cells with cardiac conduction system properties is still challenging, and the produced cell mass and quality is poor. Here, we describe the generation of cardiac cells with properties of the cardiac conduction system, called conduction system-like cells (CSLC). As a primary approach, we introduced a CrispR-Cas9-directed knockout of the NKX2-5 gene in hiPSC. NKX2-5-deficient hiPSC showed altered connexin expression patterns characteristic for the cardiac conduction system with strong connexin 40 and connexin 43 expression and suppressed connexin 45 expression. Application of differentiation protocols for ventricular- or SAN-like cells could not reverse this connexin expression pattern, indicating a stable regulation by NKX2-5 on connexin expression. The contraction behaviour of the hiPSC-derived CSLCs was compared to hiPSC-derived ventricular- and SAN-like cells. We found that the contraction speed of CSLCs resembled the expected contraction rate of human conduction system cells. Overall contraction was reduced in differentiated cells derived from NKX2-5 knockout hiPSC. Comparative transcriptomic data suggest a specification of the cardiac subtype of CSLC that is distinctly different from ventricular or pacemaker-like cells with reduced myocardial gene expression and enhanced extracellular matrix formation for improved electrical insulation. In summary, knockout of NKX2-5 in hiPSC leads to enhanced differentiation of cells with cardiac conduction system features, including connexin expression and contraction behaviour. [ABSTRACT FROM AUTHOR]

المؤلفون: Disse, Paul, Aymanns, Isabel, Ritter, Nadine, Peischard, Stefan, Korn, Lisanne, Wiendl, Heinz, Pawlowski, Matthias, Kovac, Stjepana, Meuth, Sven G., Budde, Thomas, Strutz-Seebohm, Nathalie, Wünsch, Bernhard, Seebohm, Guiscard

المساهمون: Deutsche Forschungsgemeinschaft

المصدر: Biological Chemistry ; volume 404, issue 4, page 267-277 ; ISSN 1431-6730 1437-4315

الوصف: N -Methyl- D -aspartate receptors (NMDARs) are central for learning and information processing in the brain. Dysfunction of NMDARs can play a key role in the pathogenesis of neurodegeneration and drug addiction. The development of selective NMDAR modulators represents a promising strategy to target these diseases. Among such modulating compounds are ifenprodil and its 3-benzazepine derivatives. Classically, the effects of these NMDAR modulators have been tested by techniques like two-electrode voltage clamp (TEVC), patch clamp, or fluorescence-based assays. However, testing their functional effects in complex human systems requires more advanced approaches. Here, we established a human induced pluripotent stem cell-derived (hiPSC-derived) neural cell system and proved its eligibility as a test system for investigating NMDAR modulators and pharmaceutical effects on human neurons.

الإتاحة: https://doi.org/10.1515/hsz-2022-0216Test