FMP Publications

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

All :: 2010, 2012, 2013, 2015, 2017
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All :: Ichihara*), ... , Imhof(*), Inak(*), Irsen(*), ... , Izsvak(*) 
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Neuronal Chemosensation and Osmotic Stress Response Converge in the Regulation of aqp-8 in C. elegans
Igual Gil(*), C., Jarius(*), M., von Kries, J. P.; Rohlfing(*), A. K.
Frontiers in physiology, 8:380

Tags: Screening Unit (von Kries)

Abstract: Aquaporins occupy an essential role in sustaining the salt/water balance in various cells types and tissues. Here, we present new insights into aqp-8 expression and regulation in Caenorhabditis elegans. We show, that upon exposure to osmotic stress, aqp-8 exhibits a distinct expression pattern within the excretory cell compared to other C. elegans aquaporins expressed. This expression is correlated to the osmolarity of the surrounding medium and can be activated physiologically by osmotic stress or genetically in mutants with constitutively active osmotic stress response. In addition, we found aqp-8 expression to be constitutively active in the TRPV channel mutant osm-9(ok1677). In a genome-wide RNAi screen we identified additional regulators of aqp-8. Many of these regulators are connected to chemosensation by the amphid neurons, e.g., odr-10 and gpa-6, and act as suppressors of aqp-8 expression. We postulate from our results, that aqp-8 plays an important role in sustaining the salt/water balance during a secondary response to hyper-osmotic stress. Upon its activation aqp-8 promotes vesicle docking to the lumen of the excretory cell and thereby enhances the ability to secrete water and transport osmotic active substances or waste products caused by protein damage. In summary, aqp-8 expression and function is tightly regulated by a network consisting of the osmotic stress response, neuronal chemosensation as well as the response to protein damage. These new insights in maintaining the salt/water balance in C. elegans will help to reveal the complex homeostasis network preserved throughout species.

Disruption of the vacuolar-type H+-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes
Kissing(*), S., Rudnik(*), S., Damme(*), M., Lullmann-Rauch(*), R., Ichihara*), A., Kornak(*), U., Eskelinen(*), E. L., Jabs, S., Heeren(*), J., De Brabander(*), J. K., Haas(*), A.; Saftig(*), P.
Autophagy, 13:670-685

Tags: Physiology and Pathology of Ion Transport (Jentsch)

Abstract: The vacuolar-type H+-translocating ATPase (v-H+-ATPase) has been implicated in the amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (MTORC1), an important regulator of macroautophagy. To reveal the mechanistic links between the v-H+-ATPase and MTORC1, we destablilized v-H+-ATPase complexes in mouse liver cells by induced deletion of the essential chaperone ATP6AP2. ATP6AP2-mutants are characterized by massive accumulation of endocytic and autophagic vacuoles in hepatocytes. This cellular phenotype was not caused by a block in endocytic maturation or an impaired acidification. However, the degradation of LC3-II in the knockout hepatocytes appeared to be reduced. When v-H+-ATPase levels were decreased, we observed lysosome association of MTOR and normal signaling of MTORC1 despite an increase in autophagic marker proteins. To better understand why MTORC1 can be active when v-H+-ATPase is depleted, the activation of MTORC1 was analyzed in ATP6AP2-deficient fibroblasts. In these cells, very little amino acid-elicited activation of MTORC1 was observed. In contrast, insulin did induce MTORC1 activation, which still required intracellular amino acid stores. These results suggest that in vivo the regulation of macroautophagy depends not only on v-H+-ATPase-mediated regulation of MTORC1.

Subtype-specific block of voltage-gated K+ channels by mu-conopeptides
Leipold(*), E., Ullrich, F., Thiele(*), M., Tietze(*), A. A., Terlau(*), H., Imhof(*), D.; Heinemann(*), S. H.
Biochem. Biophys. Res. Commun., 482:1135-1140

Tags: Physiology and Pathophysiology of Ion Transport (Jentsch)

Abstract: The neurotoxic cone snail peptide mu-GIIIA specifically blocks skeletal muscle voltage-gated sodium (Na(V)1.4) channels. The related conopeptides mu-PIIIA and mu-SIIIA, however, exhibit a wider activity spectrum by also inhibiting the neuronal Na-V channels Na-V 1.2 and Na-V 1.7. Here we demonstrate that those mu-conopeptides with a broader target range also antagonize select subtypes of voltage-gated potassium channels of the K(v)1 family: mu-PIIIA and mu-SIIIA inhibited K(V)1.1 and K(V)1.6 channels in the nanomolar range, while being inactive on subtypes K(V)1.2-1.5 and K(V)2.1. Construction and electro-physiological evaluation of chimeras between K(V)1.5 and K(V)1.6 revealed that these toxins block K-V channels involving their pore regions; the subtype specificity is determined in part by the sequence close to the selectivity filter but predominantly by the so-called turret domain, i.e. the extracellular loop connecting the pore with transmembrane segment S5. Conopeptides mu-SIIIA and mu-PIIIA thus, are not specific for Na-V channels, and the known structure of some K-V channel subtypes may provide access to structural insight into the molecular interaction between-conopeptides and their target channels. (C) 2016 Elsevier Inc. All rights reserved.

Evidence for Heterodimerization and Functional Interaction of the Angiotensin Type 2 Receptor and the Receptor MAS
Leonhardt(*), J., Villela(*), D. C., Teichmann, A., Munter(*), L. M., Mayer(*), M. C., Mardahl(*), M., Kirsch(*), S., Namsolleck(*), P., Lucht(*), K., Benz(*), V., Alenina(*), N., Daniell(*), N., Horiuchi(*), M., Iwai(*), M., Multhaup(*), G., Schülein, R., Bader(*), M., Santos(*), R. A., Unger(*), T.; Steckelings(*), U. M.

Tags: Protein Trafficking (Schülein), Cellular Imaging (Wiesner)

Abstract: The angiotensin type 2 receptor (AT2R) and the receptor MAS are receptors of the protective arm of the renin-angiotensin system. They mediate strikingly similar actions. Moreover, in various studies, AT2R antagonists blocked the effects of MAS agonists and vice versa. Such cross-inhibition may indicate heterodimerization of these receptors. Therefore, this study investigated the molecular and functional interplay between MAS and the AT2R. Molecular interactions were assessed by fluorescence resonance energy transfer and by cross correlation spectroscopy in human embryonic kidney-293 cells transfected with vectors encoding fluorophore-tagged MAS or AT2R. Functional interaction of AT2R and MAS was studied in astrocytes with CX3C chemokine receptor-1 messenger RNA expression as readout. Coexpression of fluorophore-tagged AT2R and MAS resulted in a fluorescence resonance energy transfer efficiency of 10.8 +/- 0.8%, indicating that AT2R and MAS are capable to form heterodimers. Heterodimerization was verified by competition experiments using untagged AT2R and MAS. Specificity of dimerization of AT2R and MAS was supported by lack of dimerization with the transient receptor potential cation channel, subfamily C-member 6. Dimerization of the AT2R was abolished when it was mutated at cysteine residue 35. AT2R and MAS stimulation with the respective agonists, Compound 21 or angiotensin-(1-7), significantly induced CX3C chemokine receptor-1 messenger RNA expression. Effects of each agonist were blocked by an AT2R antagonist (PD123319) and also by a MAS antagonist (A-779). Knockout of a single of these receptors made astrocytes unresponsive for both agonists. Our results suggest that MAS and the AT2R form heterodimers and that-at least in astrocytes-both receptors functionally depend on each other.

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders
Lorenz(*), C., Lesimple(*), P., Bukowiecki(*), R., Zink(*), A., Inak(*), G., Mlody(*), B., Singh(*), M., Semtner(*), M., Mah(*), N., Aure(*), K., Leong(*), M., Zabiegalov(*), O., Lyras(*), E. M., Pfiffer(*), V., Fauler(*), B., Eichhorst, J., Wiesner, B., Huebner(*), N., Priller(*), J., Mielke(*), T., Meierhofer(*), D., Izsvak(*), Z., Meier(*), J. C., Bouillaud(*), F., Adjaye(*), J., Schuelke(*), M., Wanker(*), E. E., Lombes(*), A.; Prigione(*), A.
Cell stem cell,

Tags: Cellular Imaging (Wiesner)

Abstract: Mitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.


Real-time NMR monitoring of biological activities in complex physiological environments
Smith(*), M. J., Marshall(*), C. B., Theillet, F. X., Binolfi, A., Selenko, P.; Ikura(*), M.
Curr Opin Struct Biol, 32:39-47

Tags: In-Cell NMR (Selenko)

Abstract: Biological reactions occur in a highly organized spatiotemporal context and with kinetics that are modulated by multiple environmental factors. To integrate these variables in our experimental investigations of 'native' biological activities, we require quantitative tools for time-resolved in situ analyses in physiologically relevant settings. Here, we outline the use of high-resolution NMR spectroscopy to directly observe biological reactions in complex environments and in real-time. Specifically, we discuss how real-time NMR (RT-NMR) methods have delineated insights into metabolic processes, post-translational protein modifications, activities of cellular GTPases and their regulators, as well as of protein folding events.


CRIS-A Novel cAMP-Binding Protein Controlling Spermiogenesis and the Development of Flagellar Bending
Krähling(*), A. M., Alvarez(*), L., Debowski(*), K., Van(*), Q., Gunkel(*), M., Irsen(*), S., Al-Amoudi(*), A., Strünker(*), T., Kremmer(*), E., Krause, E., Voigt(*), I., Wortge(*), S., Waisman(*), A., Weyand(*), I., Seifert(*), R., Kaupp(*), U. B.; Wachten(*), D.
Plos Genet, 9

Tags: Mass Spectrometry (Krause, E.)

Abstract: The second messengers cAMP and cGMP activate their target proteins by binding to a conserved cyclic nucleotide-binding domain (CNBD). Here, we identify and characterize an entirely novel CNBD-containing protein called CRIS (cyclic nucleotide receptor involved in sperm function) that is unrelated to any of the other members of this protein family. CRIS is exclusively expressed in sperm precursor cells. Cris-deficient male mice are either infertile due to a lack of sperm resulting from spermatogenic arrest, or subfertile due to impaired sperm motility. The motility defect is caused by altered Ca2+ regulation of flagellar beat asymmetry, leading to a beating pattern that is reminiscent of sperm hyperactivation. Our results suggest that CRIS interacts during spermiogenesis with Ca2+-regulated proteins that-in mature sperm-are involved in flagellar bending.


Determination of different putative allosteric binding pockets at the lutropin receptor by using diverse drug-like low molecular weight ligands
Heitman(*), L. H., Kleinau, G., Brussee(*), J., Krause, G.; Ijzerman(*), A. P.
Mol Cell Endocrinol, 351:326-336

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

Abstract: The lutropin/choriogonadotrophin receptor (LHCGR) is a family A G protein-coupled receptor (GPCR) which binds the endogenous hormone-ligands at the large extracellular domain. In contrast, several drug-like low-molecular-weight ligands (LMWs) have been reported to interact allosterically within the seven transmembrane domain (7TMD) of the LHCGR. Here, we were interested to study the putative allosteric LHCGR binding region with focus on the determination of two pockets for LMW ligands. A library of compounds was screened for their ability to modify the binding of an allosteric radiolabeled LMW agonist [H-3]Org 43553. Further experimental and computational studies revealed that the putative binding pocket for a newly identified allosteric enhancer (LUF5419) and a previously described allosteric inhibitor (LUF5771) are overlapping and that this site is different from the Org 43553 binding site. The present study showed that these compounds are useful tools to reveal details on different allosteric binding sites located within the 7TMD of the LHCGR. (C) 2012 Elsevier Ireland Ltd. All rights reserved.


Cellular structural biology
Ito(*), Y.; Selenko, P.
Curr Opin Struc Biol, 20:640-648

Tags: In-Cell NMR (Selenko)

Abstract: While we appreciate the complexity of the intracellular environment as a general property of every living organism, we collectively lack the appropriate tools to analyze protein structures in a cellular context In-cell NMR spectroscopy represents a novel biophysical tool to investigate the conformational and functional characteristics of biomolecules at the atomic level inside live cells Here, we review recent in-cell NMR developments and provide an outlook towards future applications in prokaryotic and eukaryotic cells We hope to thereby emphasize the usefulness of in-cell NMR techniques for cellular studies of complex biological processes and for structural analyses in native environments

Effects of ACE2 inhibition in the post-myocardial infarction heart
Kim(*), M. A., Yang(*), D., Kida(*), K., Molotkova(*), N., Yeo(*), S. J., Varki(*), N., Iwata(*), M., Dalton(*), N. D., Peterson(*), K. L., Siems, W. E., Walther(*), T., Cowling(*), R. T., Kjekshus(*), J.; Greenberg(*), B.
Journal of cardiac failure, 16:777-785

Tags: Biochemical Neurobiology (Siems)

Abstract: BACKGROUND: There is evidence that angiotensin-converting enzyme 2 (ACE2) is cardioprotective. To assess this in the post-myocardial infarction (MI) heart, we treated adult male Sprague-Dawley rats with either placebo (PL) or C16, a selective ACE2 inhibitor, after permanent coronary artery ligation or sham operation. METHODS AND RESULTS: Coronary artery ligation resulting in MI between 25% to 50% of the left ventricular (LV) circumference caused substantial cardiac remodeling. Daily C16 administration from postoperative days 2 to 28 at a dose that inhibited myocardial ACE2 activity was associated with a significant increase in MI size and reduction in LV % fractional shortening. Treatment with C16 did not significantly affect post-MI increases in LV end-diastolic dimension but did inhibit increases in wall thickness and fibrosis in non-infarcted LV. On postoperative day 7, C16 had no significant effect on the increased level of apoptosis in the infarct and border zones nor did it significantly affect capillary density surrounding the MI. It did, however, significantly reduce the number of c-kit(+) cells in the border region. CONCLUSIONS: These findings support the notion that ACE2 exerts cardioprotective effects by preserving jeopardized cardiomyocytes in the border zone. The reduction in hypertrophy and fibrosis with C16, however, suggests that ACE2 activity has diverse effects on post-MI remodeling.

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Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)

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