FMP Publications

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

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References
Anchoring dipalmitoyl phosphoethanolamine to nanoparticles boosts cellular uptake and fluorine-19 magnetic resonance signal
Waiczies(*), S., Lepore(*), S., Sydow, K., Drechsler(*), S., Ku(*), M. C., Martin(*), C., Lorenz, D., Schütz, I., Reimann(*), H. M., Purfurst(*), B., Dieringer(*), M. A., Waiczies(*), H., Dathe, M., Pohlmann(*), A.; Niendorf(*), T.
Sci Rep, 5:8427
(2015)

Tags: Peptide-Lipid-Interaction/ Peptide Transport (Dathe), Molecular Pharmacology and Cell Biology (Haucke), Cellular Imaging (Wiesner)

Abstract: Magnetic resonance (MR) methods to detect and quantify fluorine ((19)F) nuclei provide the opportunity to study the fate of cellular transplants in vivo. Cells are typically labeled with (19)F nanoparticles, introduced into living organisms and tracked by (19)F MR methods. Background-free imaging and quantification of cell numbers are amongst the strengths of (19)F MR-based cell tracking but challenges pertaining to signal sensitivity and cell detection exist. In this study we aimed to overcome these limitations by manipulating the aminophospholipid composition of (19)F nanoparticles in order to promote their uptake by dendritic cells (DCs). As critical components of biological membranes, phosphatidylethanolamines (PE) were studied. Both microscopy and MR spectroscopy methods revealed a striking (at least one order of magnitude) increase in cytoplasmic uptake of (19)F nanoparticles in DCs following enrichment with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE). The impact of enriching (19)F nanoparticles with PE on DC migration was also investigated. By manipulating the nanoparticle composition and as a result the cellular uptake we provide here one way of boosting (19)F signal per cell in order to overcome some of the limitations related to (19)F MR signal sensitivity. The boost in signal is ultimately necessary to detect and track cells in vivo.

Specific binding of Clostridium perfringens enterotoxin fragment to Claudin-b and modulation of zebrafish epidermal barrier
Zhang(*), J., Ni(*), C., Yang(*), Z., Piontek, A., Chen(*), H., Wang(*), S., Fan(*), Y., Qin(*), Z.; Piontek(*), J.
Exp Dermatol, 24:605-610
(2015)

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

Abstract: Claudins (Cldn) are the major components of tight junctions (TJs) sealing the paracellular cleft in tissue barriers of various organs. Zebrafish Cldnb, the homolog of mammalian Cldn4, is expressed at epithelial cell-cell contacts and is important for regulating epidermal permeability. The bacterial toxin Clostridium perfringens enterotoxin (CPE) has been shown to bind to a subset of mammalian Cldns. In this study, we used the Cldn-binding C-terminal domain of CPE (194-319 amino acids, cCPE 194-319 ) to investigate its functional role in modulating zebrafish larval epidermal barriers. In vitro analyses show that cCPE 194-319 removed Cldn4 from epithelial cells and disrupted the monolayer tightness, which could be rescued by the removal of cCPE 194-319. Incubation of zebrafish larvae with cCPE 194-319 removed Cldnb specifically from the epidermal cell membrane. Dye diffusion analysis with 4-kDa fluorescent dextran indicated that the permeability of the epidermal barrier increased due to cCPE 194-319 incubation. Electron microscopic investigation revealed reversible loss of TJ integrity by Cldnb removal. Collectively, these results suggest that cCPE 194-319 could be used as a Cldnb modulator to transiently open the epidermal barrier in zebrafish. In addition, zebrafish might be used as an in vivo system to investigate the capability of cCPE to enhance drug delivery across tissue barriers.

Theta oscillations regulate the speed of locomotion via a hippocampus to lateral septum pathway
Bender, F., Gorbati, M., Cadavieco, M. C., Denisova, N., Gao, X., Holman, C., Korotkova, T.; Ponomarenko, A.
Nat Commun, 6:8521
(2015)

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: Hippocampal theta oscillations support encoding of an animal's position during spatial navigation, yet longstanding questions about their impact on locomotion remain unanswered. Combining optogenetic control of hippocampal theta oscillations with electrophysiological recordings in mice, we show that hippocampal theta oscillations regulate locomotion. In particular, we demonstrate that their regularity underlies more stable and slower running speeds during exploration. More regular theta oscillations are accompanied by more regular theta-rhythmic spiking output of pyramidal cells. Theta oscillations are coordinated between the hippocampus and its main subcortical output, the lateral septum (LS). Chemo- or optogenetic inhibition of this pathway reveals its necessity for the hippocampal regulation of running speed. Moreover, theta-rhythmic stimulation of LS projections to the lateral hypothalamus replicates the reduction of running speed induced by more regular hippocampal theta oscillations. These results suggest that changes in hippocampal theta synchronization are translated into rapid adjustment of running speed via the LS.

KCNQ5 K(+) channels control hippocampal synaptic inhibition and fast network oscillations
Fidzinski, P., Korotkova, T., Heidenreich, M., Maier(*), N., Schütze, S., Kobler(*), O., Zuschratter(*), W., Schmitz(*), D., Ponomarenko, A.; Jentsch, T. J.
Nat Commun, 6:6254
(2015)

Tags: Physiology and Pathology of Ion Transport (Jentsch), Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) K(+) channels dampen neuronal excitability and their functional impairment may lead to epilepsy. Less is known about KCNQ5 (Kv7.5), which also displays wide expression in the brain. Here we show an unexpected role of KCNQ5 in dampening synaptic inhibition and shaping network synchronization in the hippocampus. KCNQ5 localizes to the postsynaptic site of inhibitory synapses on pyramidal cells and in interneurons. Kcnq5(dn/dn) mice lacking functional KCNQ5 channels display increased excitability of different classes of interneurons, enhanced phasic and tonic inhibition, and decreased electrical shunting of inhibitory postsynaptic currents. In vivo, loss of KCNQ5 function leads to reduced fast (gamma and ripple) hippocampal oscillations, altered gamma-rhythmic discharge of pyramidal cells and impaired spatial representations. Our work demonstrates that KCNQ5 controls excitability and function of hippocampal networks through modulation of synaptic inhibition.

Syntaxin 1B is important for mouse postnatal survival and proper synaptic function at the mouse neuromuscular junctions
Wu(*), Y. J., Tejero(*), R., Arancillo(*), M., Vardar(*), G., Korotkova, T., Kintscher(*), M., Schmitz(*), D., Ponomarenko, A., Tabares(*), L.; Rosenmund(*), C.
Journal of neurophysiology, 114:2404-2417
(2015)

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: STX1 is a major neuronal syntaxin protein located at the plasma membrane of the neuronal tissues. Rodent STX1 has two highly similar paralogs, STX1A and STX1B, that are thought to be functionally redundant. Interestingly, some studies have shown that the distribution patterns of STX1A and STX1B at the central and peripheral nervous systems only partially overlapped, implying that there might be differential functions between these paralogs. In the current study, we generated an STX1B knockout (KO) mouse line and studied the impact of STX1B removal in neurons of several brain regions and the neuromuscular junction (NMJ). We found that either complete removal of STX1B or selective removal of it from forebrain excitatory neurons in mice caused premature death. Autaptic hippocampal and striatal cultures derived from STX1B KO mice still maintained efficient neurotransmission compared with neurons from STX1B wild-type and heterozygous mice. Interestingly, examining high-density cerebellar cultures revealed a decrease in the spontaneous GABAergic transmission frequency, which was most likely due to a lower number of neurons in the STX1B KO cultures, suggesting that STX1B is essential for neuronal survival in vitro. Moreover, our study also demonstrated that although STX1B is dispensable for the formation of the mouse NMJ, it is required to maintain the efficiency of neurotransmission at the nerve-muscle synapse.

Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs
Planells-Cases, R., Lutter, D., Guyader(*), C., Gerhards(*), N. M., Ullrich, F., Elger, D. A., Kucukosmanoglu(*), A., Xu(*), G., Voss, F. K., Reincke, S. M., Stauber, T., Blomen(*), V. A., Vis(*), D. J., Wessels(*), L. F., Brummelkamp(*), T. R., Borst(*), P., Rottenberg(*), S.; Jentsch, T. J.
EMBO J, 34:2993-3008
(2015)

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug-induced apoptosis independently from drug uptake, possibly by impairing VRAC-dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D-containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.

Simian hemorrhagic fever virus cell entry is dependent on CD163 and uses a clathrin-mediated endocytosis-like pathway
Cai(*), Y., Postnikova(*), E. N., Bernbaum(*), J. G., Yu(*), S. Q., Mazur(*), S., Deiuliis(*), N. M., Radoshitzky(*), S. R., Lackemeyer(*), M. G., McCluskey(*), A., Robinson(*), P. J., Haucke, V., Wahl-Jensen(*), V., Bailey(*), A. L., Lauck(*), M., Friedrich(*), T. C., O'Connor(*), D. H., Goldberg(*), T. L., Jahrling(*), P. B.; Kuhn(*), J. H.
J Virol, 89:844-856
(2015)

Tags: Molecular Pharmacology and Cell Biology (Haucke)

Abstract: UNLABELLED: Simian hemorrhagic fever virus (SHFV) causes a severe and almost uniformly fatal viral hemorrhagic fever in Asian macaques but is thought to be nonpathogenic for humans. To date, the SHFV life cycle is almost completely uncharacterized on the molecular level. Here, we describe the first steps of the SHFV life cycle. Our experiments indicate that SHFV enters target cells by low-pH-dependent endocytosis. Dynamin inhibitors, chlorpromazine, methyl-beta-cyclodextrin, chloroquine, and concanamycin A dramatically reduced SHFV entry efficiency, whereas the macropinocytosis inhibitors EIPA, blebbistatin, and wortmannin and the caveolin-mediated endocytosis inhibitors nystatin and filipin III had no effect. Furthermore, overexpression and knockout study and electron microscopy results indicate that SHFV entry occurs by a dynamin-dependent clathrin-mediated endocytosis-like pathway. Experiments utilizing latrunculin B, cytochalasin B, and cytochalasin D indicate that SHFV does not hijack the actin polymerization pathway. Treatment of target cells with proteases (proteinase K, papain, alpha-chymotrypsin, and trypsin) abrogated entry, indicating that the SHFV cell surface receptor is a protein. Phospholipases A2 and D had no effect on SHFV entry. Finally, treatment of cells with antibodies targeting CD163, a cell surface molecule identified as an entry factor for the SHFV-related porcine reproductive and respiratory syndrome virus, diminished SHFV replication, identifying CD163 as an important SHFV entry component. IMPORTANCE: Simian hemorrhagic fever virus (SHFV) causes highly lethal disease in Asian macaques resembling human illness caused by Ebola or Lassa virus. However, little is known about SHFV's ecology and molecular biology and the mechanism by which it causes disease. The results of this study shed light on how SHFV enters its target cells. Using electron microscopy and inhibitors for various cellular pathways, we demonstrate that SHFV invades cells by low-pH-dependent, actin-independent endocytosis, likely with the help of a cellular surface protein.

DOTAM derivatives as active cartilage-targeting drug carriers for the treatment of osteoarthritis
Hu(*), H. Y., Lim(*), N. H., Ding-Pfennigdorff(*), D., Saas(*), J., Wendt(*), K. U., Ritzeler(*), O., Nagase(*), H., Plettenburg(*), O., Schultz(*), C.; Nazare, M.
Bioconjug Chem, 26:383-388
(2015)

Tags: Medicinal Chemistry (Nazare)

Abstract: Targeted drug-delivery methods are crucial for effective treatment of degenerative joint diseases such as osteoarthritis (OA). Toward this goal, we developed a small multivalent structure as a model drug for the attenuation of cartilage degradation. The DOTAM (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide)-based model structure is equipped with the cathepsin D protease inhibitor pepstatin A, a fluorophore, and peptide moieties targeting collagen II. In vivo injection of these soluble probes into the knee joints of mice resulted in 7-day-long local retention, while the drug carrier equipped with a scrambled peptide sequence was washed away within 6-8 h. The model drug conjugate successfully reduced the cathepsin D protease activity as measured by release of GAG peptide. Therefore, these conjugates represent a promising first drug conjugate for the targeted treatment of degenerative joint diseases.

In vivo visualization of osteoarthritic hypertrophic lesions
Hu(*), H. Y., Lim(*), N. H., Juretschke(*), H. P., Ding-Pfennigdorff(*), D., Florian(*), P., Kohlmann(*), M., Kandira(*), A., von Kries(*), J. P., Saas(*), J., Rudolphi(*), K. A., Wendt(*), K. U., Nagase(*), H., Plettenburg(*), O., Nazare, M.; Schultz(*), C.
Chem Sci, 6:6256-6261
(2015)

Tags: Medicinal Chemistry (Nazare)

Abstract: Osteoarthritis (OA) is one of the most common diseases in the aging population. While disease progress in humans is monitored indirectly by X-ray or MRI, small animal OA lesions detection always requires surgical intervention and histology. Here we introduce bimodal MR/NIR probes based on cartilage-targeting 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid amide (DOTAM) that are directly administered to the joint cavity. We demonstrate applications in healthy and diseased rat joints by MRI in vivo. The same joints are inspected post-mortem by fluorescence microscopy, showing not only the precise location of the reagents but also revealing details such as focal cartilage damage and chondrophyte or osteophyte formation. This allows for determining the distinct pathological state of the disease and the regeneration capability of the animal model and will help to correctly assess the effect of potential disease modifying OA drugs (DMOADs) in the future.

Disruption of adaptor protein 2mu (AP-2mu) in cochlear hair cells impairs vesicle reloading of synaptic release sites and hearing
Jung(*), S., Maritzen, T., Wichmann(*), C., Jing(*), Z., Neef(*), A., Revelo(*), N. H., Al-Moyed(*), H., Meese(*), S., Wojcik(*), S. M., Panou(*), I., Bulut(*), H., Schu(*), P., Ficner(*), R., Reisinger(*), E., Rizzoli(*), S. O., Neef(*), J., Strenzke(*), N., Haucke, V.; Moser(*), T.
EMBO J, 34:2686-2702
(2015)

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

Abstract: Active zones (AZs) of inner hair cells (IHCs) indefatigably release hundreds of vesicles per second, requiring each release site to reload vesicles at tens per second. Here, we report that the endocytic adaptor protein 2mu (AP-2mu) is required for release site replenishment and hearing. We show that hair cell-specific disruption of AP-2mu slows IHC exocytosis immediately after fusion of the readily releasable pool of vesicles, despite normal abundance of membrane-proximal vesicles and intact endocytic membrane retrieval. Sound-driven postsynaptic spiking was reduced in a use-dependent manner, and the altered interspike interval statistics suggested a slowed reloading of release sites. Sustained strong stimulation led to accumulation of endosome-like vacuoles, fewer clathrin-coated endocytic intermediates, and vesicle depletion of the membrane-distal synaptic ribbon in AP-2mu-deficient IHCs, indicating a further role of AP-2mu in clathrin-dependent vesicle reformation on a timescale of many seconds. Finally, we show that AP-2 sorts its IHC-cargo otoferlin. We propose that binding of AP-2 to otoferlin facilitates replenishment of release sites, for example, via speeding AZ clearance of exocytosed material, in addition to a role of AP-2 in synaptic vesicle reformation.

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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 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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