A5082161323- Ion channel regulation and function
- Neuroscience and Neuropharmacology Research
- Cardiac electrophysiology and arrhythmias
- Immune Response and Inflammation
- Atherosclerosis and Cardiovascular Diseases
- Neuroinflammation and Neurodegeneration Mechanisms
- Acute Myeloid Leukemia Research
- Immunotherapy and Immune Responses
- 14-3-3 protein interactions
- Immune Cell Function and Interaction
- Barrier Structure and Function Studies
- Mitochondrial Function and Pathology
- Hematological disorders and diagnostics
- Multiple Sclerosis Research Studies
- Congenital heart defects research
- Immunodeficiency and Autoimmune Disorders
- Nicotinic Acetylcholine Receptors Study
- Hearing, Cochlea, Tinnitus, Genetics
- Cytokine Signaling Pathways and Interactions
- Polyomavirus and related diseases
- RNA and protein synthesis mechanisms
- Cardiomyopathy and Myosin Studies
- Advanced Fluorescence Microscopy Techniques
- Ion Transport and Channel Regulation
- Dental Implant Techniques and Outcomes
University Hospital Ulm
2025
University Medical Center Freiburg
2020-2023
University of Freiburg
2020-2022
University Hospital Münster
2014-2022
University of Münster
2014-2020
Consejo Superior de Investigaciones Científicas
2011-2018
Fundación Biofísica Bizkaia
2011-2018
Instituto Biofisika
2018
University of the Basque Country
2011-2015
The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the gene drive severe hematologic abnormalities and are associated with an increased risk myelodysplastic syndromes acute myeloid leukemia; however, mechanisms underlying pathophysiology deficiency remain still unclear. We developed two different mouse models that based on serial limiting donor cell transplantation (aged) haploinsufficient cells mirror symptoms deficiency. Similar to what has been observed...
Autoimmune diseases of the central nervous system (CNS) like multiple sclerosis (MS) are characterized by inflammation and demyelinated lesions in white grey matter regions. While is present at all stages MS, it more pronounced relapsing forms disease, whereas progressive MS (PMS) shows significant neuroaxonal damage atrophy. Hence, disease-modifying treatments beneficial patients with have limited success PMS. BAF312 (siponimod) a novel sphingosine-1-phosphate receptor modulator shown to...
Blood-brain barrier (BBB) integrity is necessary to maintain homeostasis of the central nervous system (CNS). NMDA receptor (NMDAR) function and expression have been implicated in BBB integrity. However, as evidenced neuroinflammatory conditions, disruption contributes immune cell infiltration propagation inflammatory pathways. Currently, our understanding pathophysiological role NMDAR signaling on endothelial cells remains incomplete. Thus, we investigated primary mouse brain microvascular...
Tauopathies are a major type of proteinopathies underlying neurodegenerative diseases. Mutations in the tau-encoding MAPT-gene lead to hereditary cases frontotemporal lobar degeneration (FTLD)-tau, which span wide phenotypic and pathological spectrum. Some these mutations, such as N279K mutation, result shift physiological 3R/4R ratio towards more aggregation prone 4R isoform. Other mutations V337M cause decrease vitro affinity tau microtubules reduced ability promote microtubule assembly....
Kv7.2 (KCNQ2) is the principal molecular component of slow voltage gated M-channel, which strongly influences neuronal excitability. Calmodulin (CaM) binds to two intracellular C-terminal segments channels, helices A and B, it required for exit from endoplasmic reticulum. However, mechanisms by CaM controls channel trafficking are currently unknown. Here we used complementary approaches explore events underlying association between their regulation Ca(2+). First, performed a fluorometric...
M-channels are voltage-gated potassium channels composed of Kv7.2-7.5 subunits that serve as important regulators neuronal excitability. Calmodulin binding is required for Kv7 channel function and mutations in Kv7.2 disrupt calmodulin cause Benign Familial Neonatal Convulsions (BFNC), a dominantly inherited human epilepsy. On the basis mutants deficient not functional, has been defined an auxiliary subunit channels. However, we have identified presumably phosphomimetic mutation S511D permits...
BH3-mimetics inhibiting anti-apoptotic BCL-2 proteins represent a novel and promising class of antitumor drugs. While the inhibitor venetoclax is already FDA-approved, BCL-XL MCL-1 inhibitors are currently in early clinical trials. To predict side effects therapeutic inhibition on human hematopoietic system, we used RNAi small molecule S63845 cord blood-derived CD34+ cells. Both approaches resulted almost complete depletion stem progenitor As consequence, maturation into different lineages...
Summary Among the multiple roles assigned to calmodulin (CaM), controlling surface expression of Kv7.2 channels by binding two discontinuous sites is a unique property this Ca2+ protein. Mutations that interfere with CaM or sequestering prevent M-channel component from exiting endoplasmic reticulum (ER), which reduces M-current density in hippocampal neurons, enhancing excitability and offering rational mechanism explain some forms benign familial neonatal convulsions (BFNC). Previously, we...
K2P 5.1 channels (also called TASK-2 or Kcnk5) have already been shown to be relevant in the pathophysiology of autoimmune disease because they are known upregulated on peripheral and central T lymphocytes multiple sclerosis (MS) patients. Moreover, overexpression vitro provokes enhanced T-cell effector functions. However, molecular mechanisms regulating intracellular channel trafficking unknown so far. Thus, aim study is elucidate lymphocytes. Using mass spectrometry analysis, we identified...
Kv7.2 and Kv7.3 are the main components of neuronal voltage-dependent M-current, which is a subthreshold potassium conductance that exerts an important control on excitability. Despite their predominantly intracellular distribution, these channels must reach plasma membrane in order to activity. Thus, we analyzed amino acid sequence identify intrinsic signals may its surface expression. Removal interlinker connecting helix A B C-terminus produces large increase number functional at membrane....
Calmodulin (CaM) binding to the AB module is critical for multiple mechanisms governing function of Kv7.2 potassium subunits, which are one main components non-inactivating K+ M-current, a key controller neuronal excitability. Structural analysis indicates that CaM N-lobe engages with helix B, whereas C-lobe anchors IQ site within A. Here we report identification novel between helices A and B assist in binding, whose sequence reminiscent TW anchoring SK2 channels. Mutations disrupt site, or...
Rats of the Wistar Albino Glaxo/Rij (WAG/Rij) strain show symptoms resembling human absence epilepsy. Thalamocortical neurons WAG/Rij rats are characterized by an increased HCN1 expression, a negative shift in Ih activation curve, and altered responsiveness to cAMP. We cloned channels from rat thalamic cDNA libraries found N-terminal deletion 37 amino acids. In addition, WAG-HCN1 has stretch six acids, directly following deletion, where wild-type sequence (GNSVCF) is changed polyserine...
Tetrameric coiled-coil structures are present in many ion channels, often adjacent to a calmodulin (CaM) binding site, although the relationship between two is not completely understood. Here we examine dynamic properties of ABCD domain located intracellular C-terminus tetrameric, voltage-dependent, potassium selective Kv7.2 channels. This encompasses CaM site formed by helices A and B, followed helix C, which linked D coiled-coil. The data reveals that stabilizes binding, promoting...
Heteromers of Kv7.2/Kv7.3 subunits constitute the main substrate neuronal M-current that limits hyper-excitability and firing frequency. Calmodulin (CaM) binding is essential for surface expression Kv7 channels, disruption this interaction leads to diseases ranging from mild epilepsy early onset encephalopathy. In study, we addressed impact a charge neutralizing mutation located at periphery helix B (K526N). We found that, CaM was impaired, although current amplitude not altered. Currents...
Abstract The immunological synapse is a transient junction that occurs when the plasma membrane of T cell comes in close contact with an APC after recognizing peptide from antigen‐MHC. interaction starts CRAC channels embedded open, flowing calcium ions into cell. To counterbalance ion influx and subsequent depolarization, K v 1.3 KCa3.1 are recruited to synapse, increasing extracellular + concentration. These processes crucial as they initiate gene expression drives activation...
The GATA2 transcription factor is a pivotal regulator of hematopoiesis. Disruptions in the gene drive severe hematologic abnormalities and are associated with an increased risk myelodysplastic syndromes acute myeloid leukemia; however, mechanisms underlying pathophysiology deficiency remain still unclear. We developed two different mouse models that based on serial limiting donor cell transplantation (aged) haploinsufficient cells mirror symptoms deficiency. Similar to what has been observed...
Hematopoiesis is regulated by several transcription factors that ensure both a proper blood cell production and the survival of immature hematopoietic stem progenitor cells (HSPCs). Among them, GATA2 plays an essential role in HSPC development differentiation, controlling gene multiple target genes. Disruption this balance caused germline monoallelic mutations leads to variable phenotypes like immunodeficiency, cytopenia, lymphedema others. Patients are at high risk develop myelodysplastic...