FMP Publications

Our publications are recorded in a searchable database since 2010, updates will be added regularly.

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The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential
Boehlen(*), A., Schwake(*), M., Dost(*), R., Kunert(*), A., Fidzinski, P., Heinemann(*), U.; Gebhardt(*), C.
Brit J Pharmacol, 168:1182-1200

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Background and Purpose KCNQ2-5 channels are voltage-gated potassium channels that regulate neuronal excitability and represent suitable targets for the treatment of hyperexcitability disorders. The effect of Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was tested on KCNQ subtypes for its ability to alter neuronal excitability and for its anticonvulsant potential. Experimental Approach The effect of 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was evaluated using whole-cell voltage-clamp recordings from CHO cells and Xenopus laevis oocytes expressing different types of KCNQ channels. Epileptiform afterdischarges were recorded in fully amygdala-kindled rats in vivo. Neuronal excitability was assessed using field potential and whole cell recording in rat hippocampus in vitro. Key Results 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a hyperpolarizing shift of the activation curve and a pronounced slowing of deactivation in KCNQ2-mediated currents, whereas KCNQ3/5 heteromers remained unaffected. The effect was also apparent in the Retigabine-insensitive mutant KCNQ2-W236L. In fully amygdala-kindled rats, it elevated the threshold for induction of afterdischarges and reduced seizure severity and duration. In hippocampal CA1 cells, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid strongly damped neuronal excitability caused by a membrane hyperpolarization and a decrease in membrane resistance and induced an increase of the somatic resonance frequency on the single cell level, whereas synaptic transmission was unaffected. On the network level, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a significant reduction of and oscillation peak power, with no significant change in oscillation frequency. Conclusion and Implications Our data indicate that 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid is a potent KCNQ activator with a selectivity for KCNQ2 containing channels. It strongly reduces neuronal excitability and displays anticonvulsant activity in vivo.

Structural and biochemical characterization of Rv2140c, a phosphatidylethanolamine-binding protein from Mycobacterium tuberculosis
Eulenburg(*), G., Higman, V. A., Diehl, A., Wilmanns(*), M.; Holton(*), S. J.
Febs Letters, 587:2936-2942

Tags: NMR-Supported Structural Biology (Oschkinat)

Abstract: Rv2140c is one of many conserved Mycobacterium tuberculosis proteins for which no molecular function has been identified. We have determined a high-resolution crystal structure of the Rv2140c gene product, which reveals a dimeric complex that shares strong structural homology with the phosphatidylethanolamine-binding family of proteins. Rv2140c forms low-millimolar interactions with a selection of soluble phosphatidylethanolamine analogs, indicating that it has a role in lipid metabolism. Furthermore, the small molecule locostatin binds to the Rv2140c ligand-binding site and also inhibits the growth of the model organism Mycobacterium smegmatis. Structured digital abstract: Rv2140c and Rv2140c bind by molecular sieving (View interaction) v2140c and Rv2140c bind by cosedimentation in solution (View interaction) Rv2140c and Rv2140c bind by x-ray crystallography (View interaction) (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists
Hoyer, I., Haas, A. K., Kreuchwig, A., Schülein, R.; Krause, G.
Biochem Soc Trans, 41:213-217

Tags: Structural Bioinformatics and Protein Design (Krause, G.), Protein Trafficking (Schülein)

Abstract: The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR.

Oligomerization of Dynamin Superfamily Proteins in Health and Disease
Faelber(*), K., Gao(*), S., Held(*), M., Posor, Y., Haucke, V., Noe(*), F.; Daumke(*), O.
Prog Mol Biol Transl, 117:411-443

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Proteins of the dynamin superfamily are mechanochemical GTPases, which mediate nucleotide-dependent membrane remodeling events. The founding member dynamin is recruited to the neck of clathrin-coated endocytic vesicles where it oligomerizes into helical filaments. Nucleotide-hydrolysis-induced conformational changes in the oligomer catalyze scission of the vesicle neck. Here, we review recent insights into structure, function, and oligomerization of dynamin superfamily proteins and their roles in human diseases. We describe in detail the molecular mechanisms how dynamin oligomerizes at membranes and introduce a model how oligomerization is linked to membrane fission. Finally, we discuss molecular mechanisms how mutations in dynamin could lead to the congenital diseases, Centronuclear Myopathy and Charcot-Marie Tooth disease.

Crimean-Congo hemorrhagic fever virus utilizes a clathrin- and early endosome-dependent entry pathway
Garrison(*), A. R., Radoshitzky(*), S. R., Kota(*), K. P., Pegoraro(*), G., Ruthel(*), G., Kuhn(*), J. H., Altamura(*), L. A., Kwilas(*), S. A., Bavari(*), S., Haucke, V.; Schmaljohn(*), C. S.
Virology, 444:45-54

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: The early events in Crimean-Congo hemorrhagic fever virus (CCHFV) have not been completely characterized. Earlier work indicated that CCHFV likely enters cells by clathrin-mediated endocytosis (CME). Here we provide confirmatory evidence for CME entry by showing that CCHFV infection is inhibited in cells treated with Pitstop 2, a drug that specifically and reversibly interferes with the dynamics of clathrin-coated pits. Additionally, we show that CCHFV infection is inhibited by siRNA depletion of the clathrin pit associated protein AP-2. Following CME entry, we show that CCHFV has a pH-dependent entry step, with virus inactivation occurring at pH 6.0 and below. To more precisely define the endosomal trafficking of CCHFV, we show for the first time that overexpression of the dominant negative forms of Rab5 protein but not Rab7 protein inhibits CCHFV infection. These results indicate that CCHFV likely enters cells through the early endosomal compalunent. Published by Elsevier Inc.

Synaptic requiem: a duet for Piccolo and Bassoon
Kononenko, N., Pechstein, A.; Haucke, V.
EMBO J, 32:920-922

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Compromised fidelity of endocytic synaptic vesicle protein sorting in the absence of stonin 2
Kononenko, N. L., Diril(*), M. K., Puchkov, D., Kintscher(*), M., Koo(*), S. J., Pfuhl(*), G., Winter(*), Y., Wienisch(*), M., Klingauf(*), J., Breustedt(*), J., Schmitz(*), D., Maritzen, T.; Haucke, V.
Proc Natl Acad Sci U S A, 110:E526-535

Tags: Molecular Pharmacology and Cell Biology (Haucke),Membrane Traffic and Cell Motility (Maritzen)

Abstract: Neurotransmission depends on the exocytic fusion of synaptic vesicles (SVs) and their subsequent reformation either by clathrin-mediated endocytosis or budding from bulk endosomes. How synapses are able to rapidly recycle SVs to maintain SV pool size, yet preserve their compositional identity, is poorly understood. We demonstrate that deletion of the endocytic adaptor stonin 2 (Stn2) in mice compromises the fidelity of SV protein sorting, whereas the apparent speed of SV retrieval is increased. Loss of Stn2 leads to selective missorting of synaptotagmin 1 to the neuronal surface, an elevated SV pool size, and accelerated SV protein endocytosis. The latter phenotype is mimicked by overexpression of endocytosis-defective variants of synaptotagmin 1. Increased speed of SV protein retrieval in the absence of Stn2 correlates with an up-regulation of SV reformation from bulk endosomes. Our results are consistent with a model whereby Stn2 is required to preserve SV protein composition but is dispensable for maintaining the speed of SV recycling.

The tortoise and the hare revisited
Kononenko, N. L., Pechstein, A.; Haucke, V.
Elife, 2:e01233

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Optogenetics and electron microscopy reveal an ultrafast mode of synaptic vesicle recycling, adding a new twist to a 40-year-old controversy.

Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate
Posor, Y., Eichhorn-Grünig, M., Puchkov, D., Schöneberg(*), J., Ullrich(*), A., Lampe, A., Müller(*), R., Zarbakhsh(*), S., Gulluni(*), F., Hirsch(*), E., Krauss, M., Schultz(*), C., Schmoranzer, J., Noe(*), F.; Haucke, V.
Nature, 499:233-+

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic(1,2). Among the seven eukaryotic phosphoinositides the best studied species is phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits(3-6). No phosphatidylinositol other than PI(4,5)P-2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by phosphatidylinositol-3-phosphates(PI(3)P)(7). How phosphatidylinositol conversion from PI(4,5)P-2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of phosphatidylinositol-3,4-bisphosphate (PI(3,4)P-2) by class II phosphatidylinositol-3-kinase C2 alpha (PI(3) K C2 alpha) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P-2 or PI(3)K C2 alpha impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P-2 by PI(3)K C2 alpha is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P-2 in endocytosis and unravel a novel discrete function of PI(3,4)P-2 in a central cell physiological process.

Greasing the synaptic vesicle cycle by membrane lipids
Puchkov, D.; Haucke, V.
Trends Cell Biol, 23:493-503

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: Neurotransmission is based on the exocytic release of neurotransmitters from synaptic vesicles (SVs) at nerve terminals and the subsequent retrieval of SV membranes. Evidence from genetic analysis of model organisms, high-resolution imaging, and biochemical studies indicate that, in addition to the well-studied function of exo-endocytic protein networks, membrane lipids and their derivatives play a key role in SV cycling. These include structural lipids such as cholesterol and sphingolipids as well as phosphoinositides (PIs), which interact with select components of the exocytic and endocytic machineries, thereby coupling both limbs of the SV cycle. Here we provide an overview of the function of lipids in SV cycling and discuss potential models of how lipids and lipid-protein interactions may regulate presynaptic function.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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13125 Berlin, Germany
+4930 94793 - 100 
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