Sonja Langmesser

University of Tuebingen, Tübingen, Baden-Württemberg, Germany

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Publications (11)30.52 Total impact

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    ABSTRACT: The second messenger cGMP controls cardiovascular and gastrointestinal homeostasis in mammals. However, its physiological relevance in the nervous system is poorly understood.1 Now, we have reported that the cGMP-dependent protein kinase type I (PRKG1) is implicated in the regulation of the timing and quality of sleep and wakefulness.2Prkg1 mutant mice showed altered distribution of sleep and wakefulness as well as reduction in rapid-eye-movement sleep (REMS) duration and in non-REMS consolidation. Furthermore, the ability to sustain waking episodes was compromised. These observations were also reflected in wheel-running and drinking activity. A decrease in electroencephalogram power in the delta frequency range (1-4 Hz) under baseline conditions was observed, which was normalized after sleep deprivation. Together with the finding that circadian clock amplitude is reduced in Prkg1 mutants these results indicate a decrease of the wake-promoting output of the circadian system affecting sleep. Because quality of sleep might affect learning we tested Prkg1 mutants in several learning tasks and find normal spatial learning but impaired object recognition memory in these animals. Our findings indicate that Prkg1 impinges on circadian rhythms, sleep and distinct aspects of learning.
    Communicative & integrative biology 08/2009; 2(4):298-301.
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    ABSTRACT: Many effects of nitric oxide (NO) are mediated by the activation of guanylyl cyclases and subsequent production of the second messenger cyclic guanosine-3',5'-monophosphate (cGMP). cGMP activates cGMP-dependent protein kinases (PRKGs), which can therefore be considered downstream effectors of NO signaling. Since NO is thought to be involved in the regulation of both sleep and circadian rhythms, we analyzed these two processes in mice deficient for cGMP-dependent protein kinase type I (PRKG1) in the brain. Prkg1 mutant mice showed a strikingly altered distribution of sleep and wakefulness over the 24 hours of a day as well as reductions in rapid-eye-movement sleep (REMS) duration and in non-REM sleep (NREMS) consolidation, and their ability to sustain waking episodes was compromised. Furthermore, they displayed a drastic decrease in electroencephalogram (EEG) power in the delta frequency range (1-4 Hz) under baseline conditions, which could be normalized after sleep deprivation. In line with the re-distribution of sleep and wakefulness, the analysis of wheel-running and drinking activity revealed more rest bouts during the activity phase and a higher percentage of daytime activity in mutant animals. No changes were observed in internal period length and phase-shifting properties of the circadian clock while chi-squared periodogram amplitude was significantly reduced, hinting at a less robust oscillator. These results indicate that PRKG1 might be involved in the stabilization and output strength of the circadian oscillator in mice. Moreover, PRKG1 deficiency results in an aberrant pattern, and consequently a reduced quality, of sleep and wakefulness, possibly due to a decreased wake-promoting output of the circadian system impinging upon sleep.
    PLoS ONE 02/2009; 4(1):e4238. · 3.53 Impact Factor
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    ABSTRACT: Circadian oscillation of clock-controlled gene expression is mainly regulated at the transcriptional level. Heterodimers of CLOCK and BMAL1 act as activators of target gene transcription; however, interactions of PER and CRY proteins with the heterodimer abolish its transcriptional activation capacity. PER and CRY are therefore referred to as negative regulators of the circadian clock. To further elucidate the mechanism how positive and negative components of the clock interplay, we characterized the interactions of PER2, CRY1 and CRY2 with BMAL1 and CLOCK using a mammalian two-hybrid system and co-immunoprecipitation assays. Both PER2 and the CRY proteins were found to interact with BMAL1 whereas only PER2 interacts with CLOCK. CRY proteins seem to have a higher affinity to BMAL1 than PER2. Moreover, we provide evidence that PER2, CRY1 and CRY2 bind to different domains in the BMAL1 protein. The regulators of clock-controlled transcription PER2, CRY1 and CRY2 differ in their capacity to interact with each single component of the BMAL1-CLOCK heterodimer and, in the case of BMAL1, also in their interaction sites. Our data supports the hypothesis that CRY proteins, especially CRY1, are stronger repressors than PER proteins.
    BMC Molecular Biology 02/2008; 9:41. · 2.80 Impact Factor
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    ABSTRACT: Cholecystokinin (CCK) is one of the most abundant neuropeptides in the central nervous system (CNS) where it promotes important functions by activation of receptors CCK1 and CCK2. Our aim was to investigate CCK receptors expression and their downstream intracellular signaling in immortalized rat brain neuroblasts. Results show that CCK1 and CCK2 receptor mRNAs and CCK2 receptor protein are expressed in neuroblasts. CCK incubation of neuroblasts leads to stimulation in a time-dependent manner of several signaling pathways, such as tyrosine phosphorylation of adaptor proteins paxillin and p130(Cas), phosphorylation of p44/p42 ERKs as well as PKB (Ser473). Moreover, CCK-8 stimulates the DNA-binding activity of the transcription factor AP-1. The CCK2 receptor agonist gastrin stimulates ERK1/2 phosphorylation in a comparable degree as CCK does. ERK1/2 phosphorylation activated by CCK-8 was markedly inhibited by the CCK2 receptor antagonist CR2945. Incubation for 48 h with CCK-8 increases neuroblasts viability in a similar degree as EGF. In summary, our data clearly identify CCK1 and CCK2 receptor mRNAs and CCK2 receptor protein in brain neuroblasts and show that incubation with CCK promotes cell proliferation and activates the phosphorylation of survival transduction pathways. Stimulation of ERK1/2 phosphorylation by CCK is mainly mediated by the CCK2 receptor. Moreover, this work might provide a novel model of proliferating neuronal cells to further study the biochemical mechanisms by which the neuropeptide CCK exerts its actions in the CNS.
    Journal of Cellular Biochemistry 04/2007; 100(4):851-64. · 3.06 Impact Factor
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    BMC Pharmacology 01/2007;
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    ABSTRACT: The NF2 gene encodes the tumour suppressor protein merlin. The mutation of a single allele of this gene causes the autosomal dominantly inherited disease neurofibromatosis type 2 (NF2), which is characterized mainly by vestibular schwannoma carrying a second hit mutation. Complete lack of merlin is also found in spontaneous schwannomas and meningiomas. As the events leading to schwannoma development are largely unknown we investigated the differences in gene expression between schwannoma cells from NF2 patients and normal human primary Schwann cells by cDNA array analysis. We identified 41 genes whose expression levels differed by more than factor 2. Most of these clones were corroborated by real-time reverse transcription polymerase chain reaction analysis. By this method a total of seven genes with increased and seven genes with decreased mRNA levels in schwannoma compared with normal Schwann cells could be identified. Regulated clones, some of which not been described in Schwann cells earlier, included matrix metalloproteinase's, growth factors, growth factor receptors and tyrosine kinases.
    Neuropathology and Applied Neurobiology 01/2007; 32(6):605-14. · 4.84 Impact Factor
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    Sonja Langmesser, Urs Albrecht
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    ABSTRACT: A functional circadian clock has long been considered a selective advantage. Accumulating evidence shows that the clock coordinates a variety of physiological processes in order to schedule them to the optimal time of day and thus to synchronize metabolism to changes in external conditions. In mitochondria, both metabolic and cellular defense mechanisms are carefully regulated. Abnormal clock function, might influence mitochondrial function, resulting in decreased fitness of an organism.
    Chronobiology International 02/2006; 23(1-2):151-7. · 4.35 Impact Factor
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    ABSTRACT: We have previously shown that lovastatin induces apoptosis in spontaneously immortalized rat brain neuroblasts. Focal adhesion proteins and protein kinase Cdelta (PKCdelta) have been implicated in the regulation of apoptosis. We found that lovastatin exposure induced focal adhesion kinase, Crk-associated substrate (p130(Cas)), PKCdelta cleavage and caspase-3 activation in a concentration-dependent manner. Lovastatin effects were fully prevented by mevalonate. The cleavage of p130(Cas) was almost completely inhibited by z-DEVD-fmk, a specific caspase-3 inhibitor, and z-VAD-fmk, a broad spectrum caspase inhibitor, indicating that cleavage is mediated by caspase-3. In contrast, the lovastatin-induced cleavage of PKCdelta was only blocked by z-VAD-fmk suggesting that PKCdelta cleavage is caspase-dependent but caspase-3-independent. Additionally, z-VAD-fmk partially prevented lovastatin-induced neuroblast apoptosis. The present data show that lovastatin may induce neuroblast apoptosis by both caspase-dependent and independent pathways. These findings may suggest that the caspase-dependent component leading to the neuroblast cell death is likely to involve the cleavage of focal adhesion proteins and PKCdelta, which may be partially responsible for some biochemical features of neuroblast apoptosis induced by lovastatin.
    FEBS Journal 02/2006; 273(1):1-13. · 4.25 Impact Factor
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    BMC Pharmacology 01/2005;
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    BMC Pharmacology 01/2005;
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    ABSTRACT: Schwann cells lacking the tumor-suppressor-protein merlin tend in man to build benign tumors (schwannoma). We observed that characteristic features of these cells which are relevant to tumorigenicity resemble those described in cells with high Rac activity. Moreover this small GTPase also phosphorylates merlin via PAK activation. We hypothesized that merlin deficiency might cause an activation of Rac and its dependent signaling pathways, in particular the pro-tumorigenic JNK pathway. We show an enhanced activation of Rac1 in primary human schwannoma cells, find both Rac and its effector PAK at the membrane where they colocalize, and describe increased levels of phosphorylated JNK in the nucleus of these cells. Further we describe regulation at post-transcriptional level with upregulated protein, but not mRNA levels for Rac1, and JNK1/2. We conclude that merlin regulates Rac activation, and suggest that this is important for human schwannoma cell dedifferentiation.
    Human Molecular Genetics 07/2003; 12(11):1211-21. · 7.69 Impact Factor

Publication Stats

187 Citations
30.52 Total Impact Points

Institutions

  • 2009
    • University of Tuebingen
      • Interfaculty Institute for Biochemistry
      Tübingen, Baden-Württemberg, Germany
  • 2005–2009
    • Université de Fribourg
      • Département de médecine
      Fribourg, FR, Switzerland
  • 2007
    • Universidad de Extremadura
      • Departamento de Bioquímica, Biología Molecular y Genética
      Cáceres, Extremadura, Spain