FMP Publications

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

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References
Sulindac Sulfide Induces the Formation of Large Oligomeric Aggregates of the Alzheimer's Disease Amyloid-beta Peptide Which Exhibit Reduced Neurotoxicity
Prade(*), E., Barucker(*), C., Sarkar(*), R., Althoff-Ospelt(*), G., Lopez del Amo, J. M., Hossain(*), S., Zhong(*), Y., Multhaup(*), G.; Reif(*), B.
Biochemistry, 55:1839-1849
(2016)

Tags: Solid-State NMR Spectroscopy (Reif)

Abstract: Alzheimer's disease is characterized by deposition of the amyloid beta-peptide (Abeta) in brain tissue of affected individuals. In recent years, many potential lead structures have been suggested that can potentially be used for diagnosis and therapy. However, the mode of action of these compounds is so far not understood. Among these small molecules, the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide received a lot of attention. In this manuscript, we characterize the interaction between the monomeric Abeta peptide and the NSAID sulindac sulfide. We find that sulindac sulfide efficiently depletes the pool of toxic oligomers by enhancing the rate of fibril formation. In vitro, sulindac sulfide forms colloidal particles which catalyze the formation of fibrils. Aggregation is immediate, presumably by perturbing the supersaturated Abeta solution. We find that sulindac sulfide induced Abeta aggregates are structurally homogeneous. The C-terminal part of the peptide adopts a beta-sheet structure, whereas the N-terminus is disordered. The salt bridge between D23 and K28 is present, similar as in wild type fibril structures. (13)C-(19)F transferred echo double resonance experiments suggest that sulindac sulfide colocalizes with the Abeta peptide in the aggregate.

Cannabinoid Type 2 Receptors Mediate a Cell Type-Specific Plasticity in the Hippocampus
Stempel(*), A. V., Stumpf(*), A., Zhang(*), H. Y., Ozdogan(*), T., Pannasch(*), U., Theis(*), A. K., Otte(*), D. M., Wojtalla(*), A., Racz(*), I., Ponomarenko, A., Xi(*), Z. X., Zimmer(*), A.; Schmitz(*), D.
Neuron, 90:795-809
(2016)

Tags: Behavioral Neurodynamics (Korotkova/Ponomarenko)

Abstract: Endocannabinoids (eCBs) exert major control over neuronal activity by activating cannabinoid receptors (CBRs). The functionality of the eCB system is primarily ascribed to the well-documented retrograde activation of presynaptic CB1Rs. We find that action potential-driven eCB release leads to a long-lasting membrane potential hyperpolarization in hippocampal principal cells that is independent of CB1Rs. The hyperpolarization, which is specific to CA3 and CA2 pyramidal cells (PCs), depends on the activation of neuronal CB2Rs, as shown by a combined pharmacogenetic and immunohistochemical approach. Upon activation, they modulate the activity of the sodium-bicarbonate co-transporter, leading to a hyperpolarization of the neuron. CB2R activation occurred in a purely self-regulatory manner, robustly altered the input/output function of CA3 PCs, and modulated gamma oscillations in vivo. To conclude, we describe a cell type-specific plasticity mechanism in the hippocampus that provides evidence for the neuronal expression of CB2Rs and emphasizes their importance in basic neuronal transmission.

Structural rearrangement of the intracellular domains during AMPA receptor activation
Zachariassen(*), L. G., Katchan, L., Jensen(*), A. G., Pickering(*), D. S., Plested, A. J.; Kristensen(*), A. S.
Proc Natl Acad Sci U S A, 113:E3950-3959
(2016)

Tags: Molecular Neuroscience and Biophysics (Plested)

Abstract: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are ligand-gated ion channels that mediate the majority of fast excitatory neurotransmission in the central nervous system. Despite recent advances in structural studies of AMPARs, information about the specific conformational changes that underlie receptor function is lacking. Here, we used single and dual insertion of GFP variants at various positions in AMPAR subunits to enable measurements of conformational changes using fluorescence resonance energy transfer (FRET) in live cells. We produced dual CFP/YFP-tagged GluA2 subunit constructs that had normal activity and displayed intrareceptor FRET. We used fluorescence lifetime imaging microscopy (FLIM) in live HEK293 cells to determine distinct steady-state FRET efficiencies in the presence of different ligands, suggesting a dynamic picture of the resting state. Patch-clamp fluorometry of the double- and single-insert constructs showed that both the intracellular C-terminal domain (CTD) and the loop region between the M1 and M2 helices move during activation and the CTD is detached from the membrane. Our time-resolved measurements revealed unexpectedly complex fluorescence changes within these intracellular domains, providing clues as to how posttranslational modifications and receptor function interact.

An Alignment Medium for Measuring Residual Dipolar Couplings in Pure DMSO: Liquid Crystals from Graphene Oxide Grafted with Polymer Brushes
Zong(*), W., Li(*), G. W., Cao(*), J. M., Lei(*), X., Hu(*), M. L., Sun, H., Griesinger(*), C.; Tan(*), R. X.
Angew Chem Int Ed Engl, 55:3690-3693
(2016)

Tags: Computational Chemistry and Protein Design (Kühne)

Abstract: Residual dipolar couplings (RDCs) have attracted attention in light of their great impact on the structural elucidation of organic molecules. However, the effectiveness of RDC measurements is limited by the shortage of alignment media compatible with widely used organic solvents, such as DMSO. Herein, we present the first liquid crystal (LC) based alignment medium that is compatible with pure DMSO, thus enabling RDC measurements of polar and intermediate polarity molecules. The liquid crystals were obtained by grafting polymer brushes onto graphene oxide (GO) using free radical polymerization. The resulting new medium offers several advantages, such as absence of background signals, narrow line shapes, and tunable alignment. Importantly, this medium is compatible with pi-conjugated molecules. Moreover, sonication-induced fragmentation can reduce the size of GO sheets. The resulting anisotropic medium has moderate alignment strength, which is a prerequisite for an accurate RDC measurement.

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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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info(at)fmp-berlin.de

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