A5030391877- Mitochondrial Function and Pathology
- Ion channel regulation and function
- Cardiac electrophysiology and arrhythmias
- ATP Synthase and ATPases Research
- Neuroscience and Neuropharmacology Research
- Physiological and biochemical adaptations
- Zebrafish Biomedical Research Applications
- Ion Channels and Receptors
- Neurobiology and Insect Physiology Research
- Adipose Tissue and Metabolism
- Cardiomyopathy and Myosin Studies
- Metabolism and Genetic Disorders
- Asthma and respiratory diseases
- RNA and protein synthesis mechanisms
- Calcium signaling and nucleotide metabolism
- Respiratory and Cough-Related Research
- Congenital heart defects research
- Receptor Mechanisms and Signaling
- Cardiovascular Effects of Exercise
- Plant Micronutrient Interactions and Effects
- Sleep and Wakefulness Research
- Pain Mechanisms and Treatments
- Metabolomics and Mass Spectrometry Studies
- Dietary Effects on Health
- Child and Adolescent Health
Ludwig-Maximilians-Universität München
2014-2024
LMU Klinikum
2017-2024
German Centre for Cardiovascular Research
2021-2022
German Center for Lung Research
2019-2020
Institute of Pharmacology
2018-2020
University of California, Los Angeles
2012-2015
Innsbruck Medical University
2005-2010
Laboratory of Molecular Genetics
2010
University of Pennsylvania
2005
Universität Innsbruck
2004
In recent years, there has been a vast increase in structural and functional understanding of VDAC1, but VDAC2 -3 have understudied despite having many unique phenotypes. One reason for the paucity biochemical characterization isoforms stems from inability obtaining purified, protein. Here we demonstrate expression, isolation, basic zebrafish (zfVDAC2). Further, resolved structure zfVDAC2 at 2.8 Å resolution, revealing crystallographic dimer. The dimer orientation was confirmed solution by...
Ion selectivity is a defining feature of given ion channel and considered immutable. Here we show that the lysosomal TPC2, which hotly debated (Calcraft et al., 2009; Guo 2017; Jha 2014; Ruas 2015; Wang 2012), depends on activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One these evoked robust Ca2+-signals non-selective cation currents, other weaker Na+-selective currents. These properties were mirrored by Ca2+-mobilizing messenger, NAADP...
Homozygous zebrafish of the mutant relaxed ( red ts25 ) are paralyzed and die within days after hatching. A significant reduction intramembrane charge movements lack depolarization-induced but not caffeine-induced Ca 2+ transients suggested a defect in skeletal muscle dihydropyridine receptor (DHPR). Sequencing DHPR cDNAs indicated that α 1S subunit is normal, whereas β 1a harbors single point mutation resulting premature stop. Quantitative RT-PCR revealed mutated gene transcribed, Western...
Tightly regulated Ca2+ homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of handling, we performed chemical suppressor screen on zebrafish tremblor embryos, which suffer from extrusion defects. Efsevin was identified based its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds VDAC2, potentiates mitochondrial uptake and accelerates transfer intracellular stores into mitochondria. In cardiomyocytes, restricts...
TRPM6 and its homologue TRPM7 are α-kinase-coupled divalent cation-selective channels activated upon reduction of cytosolic levels Mg2+ Mg·ATP. is vital for organismal balance. However, mechanistically the cellular role functional nonredundancy remain incompletely understood. Comparative analysis native currents in primary cells from TRPM6- versus TRPM7-deficient mice supported concept that primarily functions as a constituent heteromeric TRPM6/7 channels. heterologous expression human...
Ischemia/reperfusion-induced edema (IRE), one of the most significant causes mortality after lung transplantation, can be mimicked ex vivo in isolated perfused mouse lungs (IPL). Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel studied endothelium; however, its role epithelium remains elusive. Here, we show enhanced IRE TRPV4-deficient (TRPV4-/-) IPL compared with that WT controls, indicating protective TRPV4 maintenance alveolar epithelial barrier. By...
Abstract Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities homeostasis often leads electrical contractile dysfunction can cause dilated cardiomyopathy heart failure. However, the specific of VDAC2 intracellular dynamics cardiac function not well understood. To elucidate homeostasis, we generated ventricular myocyte-specific developmental deletion Vdac2 mice. Our results...
The paralyzed zebrafish strain relaxed carries a null mutation for the skeletal muscle dihydropyridine receptor (DHPR) β1a subunit. Lack of results in (i) reduced membrane expression pore forming DHPR α1S subunit, (ii) elimination charge movement, and (iii) impediment arrangement DHPRs groups four (tetrads) opposing ryanodine (RyR1), structural prerequisite muscle-type excitation-contraction (EC) coupling. In this study we used larvae isolated myotubes as systems to discriminate specific...
During skeletal muscle excitation-contraction (EC) coupling, membrane depolarizations activate the sarcolemmal voltage-gated L-type Ca 2+ channel (Ca V 1.1). 1.1 in turn triggers opening of sarcoplasmic release (RyR1) via interchannel protein–protein interaction to for myofibril contraction. Simultaneously this EC coupling process, a small and slowly activating inward current through is found mammalian myotubes. The role influx, which not immediately required still enigmatic. Interestingly,...
To identify the genetic locus responsible for malignant hyperthermia susceptibility (MHS) in an Italian family, we performed linkage analysis to recognized MHS loci. All individuals showed cosegregation of informative markers close voltage-dependent Ca(2+) channel (Ca(V)) α(1S)-subunit gene (CACNA1S) with logarithm odds (LOD)-score values that matched or approached maximal possible value this family. This is particularly interesting, because so far was mapped >178 different positions on...
Cardiovascular disease-related deaths frequently arise from arrhythmias, but treatment options are limited due to perilous side effects of commonly used antiarrhythmic drugs. Cardiac rhythmicity strongly depends on cardiomyocyte Ca2+ handling and prevalent cardiac diseases causally associated with perturbations in intracellular handling. Therefore, transporters lead candidate structures for novel safer therapies. Mitochondria mitochondrial transport proteins important regulators Here, the...
Treatment of cardiac arrhythmia remains challenging due to severe side effects common anti-arrhythmic drugs. We previously demonstrated that mitochondrial Ca2+ uptake in cardiomyocytes represents a promising new candidate structure for safer drug therapy. However, druggable agonists suitable preclinical and clinical studies are still missing.Herewe screened 727 compounds with history use human trials three-step screening approach. As primary platform we used permeabilized HeLa cell-based...
Brain and muscle ARNT-like protein-1 (BMAL-1) is an important component of the cellular circadian clock. Proteins such as epidermal (EGF) or nerve growth factor (NGF) affect clock via extracellular signal–regulated kinases-1/2 (ERK-1/2) in NIH3T3 neuronal stem cells, but no data are available for insulin-like factor-1 (IGF-1). The hypothalamus expresses receptors all three factors, acts a central pacemaker, releases hormones fashion. However, little known about factor–induced modulation gene...
Background and Purpose The synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity shown be dependent on the voltage‐dependent anion channel 2 (VDAC2) outer mitochondrial membrane. Here, we investigated molecular mechanism efsevin–VDAC2 interaction. Experimental Approach To evaluate functional interaction VDAC2, measured currents through recombinant VDAC2 planar...
In skeletal muscle excitation-contraction (EC) coupling the sarcolemmal L-type Ca(2+) channel or 1,4-dihydropyridine receptor (DHPR) transduces membrane depolarization signal to sarcoplasmic release RyR1 via protein-protein interaction. While it is evident that pore-forming and voltage-sensing DHPRalpha(1S) subunit essential for this process, intracellular DHPRbeta(1a) was also shown be indispensable. We previously found beta(1a) target DHPR into groups of four (tetrads) opposite...
The v-type ATPase is a membrane anchored, multi-subunit proton pump, which in freshwater fish appears to play major role ionoregulative processes the apical of specialized gill cells. Very little known about free-living embryos and larvae that are exposed hypo-osmotic conditions with spawning but do not have their gills fully developed. By using reverse transcriptase-polymerase chain reaction immunological methods, we could demonstrate presence two isoforms subunit B this early development...
Mitochondria critically regulate a range of cellular processes including bioenergetics, metabolism, apoptosis, and Ca2+ signaling. The voltage-dependent anion channel (VDAC) functions as passageway for the exchange ions, Ca2+, across outer mitochondrial membrane. In cardiomyocytes, genetic or pharmacological activation isoform 2 VDAC (VDAC2) effectively potentiates uptake suppresses overload-induced arrhythmogenic events. However, molecular mechanisms by which VDAC2 controls transport...
reasoning as a critical component of clinical has been understudied in medical education contrast to the well-established field diagnostic reasoning. This resonates lack comprehensive understanding cognitive processes involved and deficit research promote intervention skills future clinicians. In this commentary, we present conceptual framework for that includes four phases: generating, selecting, implementing, evaluating interventions. The conceptualization highlights such developing...