A5040569338- Nitric Oxide and Endothelin Effects
- Receptor Mechanisms and Signaling
- Phosphodiesterase function and regulation
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Eicosanoids and Hypertension Pharmacology
- Cholinesterase and Neurodegenerative Diseases
- Pulmonary Hypertension Research and Treatments
- Reproductive Biology and Fertility
- Adenosine and Purinergic Signaling
- Hemoglobin structure and function
- Sphingolipid Metabolism and Signaling
- Photoreceptor and optogenetics research
- Renin-Angiotensin System Studies
- Platelet Disorders and Treatments
- Erythrocyte Function and Pathophysiology
- Neurobiology and Insect Physiology Research
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Cellular transport and secretion
- Atherosclerosis and Cardiovascular Diseases
- Antiplatelet Therapy and Cardiovascular Diseases
- Circadian rhythm and melatonin
Bayer (Germany)
2013-2025
University of Göttingen
2016
University Hospital Heidelberg
2016
Universitätsmedizin Göttingen
2016
Inserm
2016
Université Paris-Saclay
2016
Université Paris-Sud
2016
Heidelberg University
2016
Bayer (United States)
2005-2012
Institut für Hämatopathologie Hamburg
1992-1994
Abstract A large variety of potassium channels is involved in regulating integration and transmission electrical signals the nervous system. Different types neurons, therefore, require specific patterns channel subunit expression regulation coassembly into heteromultimeric channels, as well subunit‐specific sorting segregation. This was investigated by studying detail six different α‐subunits voltage‐gated rat hippocampus, cerebellum, olfactory bulb spinal cord, combining situ hybridization...
Tissue expression and distribution of the high-conductance Ca(2+)- activated K+ channel Slo was investigated in rat brain by immunocytochemistry, situ hybridization, radioligand binding using novel high-affinity (Kd 22 pM) ligand [3H]iberiotoxin-D19C ([3H]IbTX-D19C), which is an analog selective maxi-K peptidyl blocker IbTX. A sequence-directed antibody directed against revealed a 125 kDa polypeptide Western blotting precipitated specifically bound [3H]IbTX-D19C solubilized membranes....
1. Soluble guanylyl cyclase (sGC) is the only proven receptor for ubiquitous biological messenger nitric oxide (NO) and intimately involved in many signal transduction pathways, most notably regulating vascular tone platelet function. sGC a heterodimeric (alpha/ss) protein that converts GTP to cyclic GMP; NO binds its prosthetic haem group. Here, we report discovery of novel activating compound, interaction with previously unrecognized regulatory site therapeutic implications. 2. Through...
Soluble guanylate cyclase (sGC) is a key signal-transduction enzyme activated by nitric oxide (NO). Impairments of the NO-sGC signaling pathway have been implicated in pathogenesis cardiovascular and other diseases. Direct stimulation sGC represents promising therapeutic strategy particularly for treatment pulmonary hypertension (PH), disabling disease associated with poor prognosis. Previous stimulators such as pyrazolopyridines BAY 41-2272 41-8543 demonstrated beneficial effects...
Significance Sensory photoreceptors not only enable organisms to derive spatial and temporal cues from incident light but also provide the basis for optogenetics, which denotes manipulation by of living systems with supreme resolution. To expand scope we have engineered light-activated phosphodiesterase LAPD, degrades ubiquitous second messengers cAMP cGMP in a red-light–stimulated manner. Both are key regulation manifold physiological responses, LAPD now augurs red-light control over these...
The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of in other cardiovascular indications is limited by short half-life, necessitating three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able decrease oxidative metabolism...
In mammals, the meiotic cell cycle of oocytes starts during embryogenesis and then pauses. Much later, in preparation for fertilization, within preovulatory follicles resume meiosis response to luteinizing hormone (LH). Before LH stimulation, arrest is maintained by diffusion cyclic (c)GMP into oocyte from surrounding granulosa cells, where it produced guanylyl cyclase natriuretic peptide receptor 2 (NPR2). rapidly reduces production cGMP, but how this occurs unknown. Here, using rat...
Sphingosine-1-phosphate (S1P) is a signaling lysolipid critical to heart development, immunity, and hearing. Accordingly, mutations in the S1P transporter SPNS2 are associated with reduced white cell count hearing defects. also exports S1P-mimicking FTY720-P (Fingolimod) thereby central pharmacokinetics of this drug when treating multiple sclerosis. Here, we use combination cryo-electron microscopy, immunofluorescence, vitro binding vivo export assays, molecular dynamics simulations probe...
Soluble guanylate cyclase (sGC), a heterodimeric hemeprotein, is the only receptor for biological messenger nitric oxide (NO) identified to date and intimately involved in various signal transduction pathways. By using recently discovered NO- heme-independent sGC activator BAY 58-2667 novel cGMP reporter cell, we could distinguish between heme-containing heme-free an intact cellular system. Using these tools, invariant amino acids tyrosine 135 arginine 139 of β1-subunit as crucially...
We report here the in vitro characterization of 1-(2-chlorophenyl)-6-[(2<i>R</i>)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidine-4-one (BAY 73-6691), first potent and selective inhibitor phosphodiesterase 9 (PDE9), which is currently under preclinical development for treatment Alzheimer9s disease. This compound selectively inhibits human (IC<sub>50</sub> = 55 nM) murine 100 PDE9 activity shows only moderate against other cyclic nucleotide-specific...
A rat brain cDNA (Raw3) related to the Drosophila Show K* channel family has been characterized, Raw3 cRNA leads formation of TEA‐insensitive, fast inactivating (A‐type) channels when injected into Xenopus leavis oocytes. have markedly different properties from previously cloned A‐type RCK4, operate in positive voltage range.
Liver cirrhosis is a chronic disease with high mortality rate and need for effective pharmacological intervention. The fibrotic remodelling of liver tissue crucially dependent on hepatic stellate cell activation. Activation cells reduced by an increase in cyclic guanosine monophosphate (cGMP). Stable cGMP analogues also reduce the contractile response cells. However, production downregulated cirrhotic due to activity endothelial nitric oxide synthase.Here we report that novel activator...
Phosphodiesterase 2 is a dual substrate esterase, which has the unique property to be stimulated by cGMP, but primarily hydrolyzes cAMP. Myocardial phosphodiesterase upregulated in human heart failure, its role unknown.To explore of cardiac function, propensity arrhythmia, and myocardial infarction.Pharmacological inhibition (BAY 60-7550, BAY) led significant positive chronotropic effect on top maximal β-adrenoceptor activation healthy mice. Under pathological conditions induced chronic...
Herein we describe the discovery, mode of action, and preclinical characterization soluble guanylate cyclase (sGC) activator runcaciguat. The sGC enzyme, via formation cyclic guanosine monophoshphate, is a key regulator body tissue homeostasis. activators with their unique action are activating oxidized heme-free therefore NO-unresponsive form sGC, which formed under oxidative stress. first generation like cinaciguat or ataciguat exhibited limitations were discontinued. We overcame...
Voltage-gated K+ channels in the mammalian brain are functionally heterogeneous. Mechanisms which may underlie heterogeneity expression of multiple channel subunit genes, alternative splicing and formation heteromultimers from different subunits. To examine molecular basis regional cell-specific rat situ hybridization techniques were used. The transcript distribution patterns 11 cloned genes encoding both slow- fast-inactivating four gene families examined at stages development. results show...
A novel potassium channel β‐subunit (K v β3) was cloned from rat brain being the third member of a K β subunit gene family. It is protein 403 amino acid residues with 68% sequence homology to β1.1. β3 primarily expressed in having distribution distinct those β1.1 and β2. This also has long N‐terminal structure induces inactivation deleted 1.4 but not other members 1 Similarly β1.1, β3‐induced regulated by intracellular redox potential.
Cysteinyl leukotrienes (CysLTs) have been implicated in the pathophysiology of inflammatory and cardiovascular disorders. Their actions are mediated by CysLT(1) CysLT(2) receptors. Here we report discovery 3-({[(1S,3S)-3-carboxycyclohexyl]amino}carbonyl)-4-(3-{4-[4-(cyclo-hexyloxy)butoxy]phenyl}propoxy) benzoic acid (HAMI3379), first potent selective receptor antagonist.Pharmacological characterization HAMI3379 was performed using stably transfected cell lines, isolated,...
Conventional drug design embraces the "one gene, one drug, disease" philosophy. Polypharmacology, which focuses on multi-target drugs, has emerged as a new paradigm in discovery. The rational of drugs that act via polypharmacological mechanisms can produce compounds exhibit increased therapeutic potency and against resistance is less likely to develop. Additionally, identifying multiple protein targets also critical for side-effect prediction. One third potential fail clinical trials or are...
In the female reproductive tract, mammalian sperm undergo a regulated sequence of prefusion changes that "prime" for fertilization. Among least understood these complex processes are molecular mechanisms underlie guidance by environmental chemical cues. A "hard-wired" Ca2+ signaling strategy orchestrates specific motility patterns according to given functional requirements is an emerging concept regulation swimming behavior. The players involved, spatiotemporal characteristics such...
AVP and atrial natriuretic peptide (ANP) have opposite effects in the kidney. induces antidiuresis by insertion of aquaporin-2 (AQP2) water channels into plasma membrane collecting duct principal cells. ANP acts as a diuretic factor. An ANP- nitric oxide (NO)/soluble guanylate cyclase (sGC)-induced AQP2 is reported from different models. However, functional data on missing. We used primary cultured inner medullary (IMCD) cells digital holographic microscopy, calcein-quenching measurements,...