Trafficking of intracellular membrane vesicles (endosomes and lysosomes) involve the formation, fusion and fission of vesicles as well as their tight interaction with filaments of the cytoskeleton and associated motor proteins. These processes are fundamental for life, occur in every cell of the body and collectively regulate intracellular logistics, signaling and intra- and intercellular communication. Defects in endosomal trafficking lead to various diseases such as metabolic disorders, infection, tumor development and growth, neurodegenerative and cardiovascular diseases. The membranes of intracellular vesicles of the endo-lysosomal system contain a variety of ion channels, which control ion homeostasis (including pH control) of the vesicular lumen and the peri-vesicular microenvironment. Our group is particularly interested in two pore channels (TPC1 and TPC2) and transient receptor potential (TRP) mucolipin channels TRPML1,2,3 that are localized in endo-lysosomal vesicles. In order to characterize the function of these channels in their specific intracellular vesicle system, we use an advanced patch clamp technique for direct current recording from isolated and enlarged endo-lysosomal vesicles. This and other methods helped to identify the role of TPC2 channels for hepatic and systemic lipoprotein and cholesterol homeostasis, for endo-lysosomal trafficking and cytosolic release of the Ebola virus, as well as for hair pigmentation. Currently, we focus on the function of TPC and TRPML channels in the cardiovascular system and in virus infection, and furthermore unravel the channels’ basic gating properties.

 

PI: PD Dr. M. Fischer, Dr. M. Klein, Dr. J. de la Roche, Dr. M. Schänzler

Cardiovascular diseases (CVDs) are the number one cause of death worldwide. In fact, more people die annually from CVDs than from any other cause. Current calculations predict that by 2030 23.6 million people will die from CVDs. It is therefore essential to understand the underlying mechanisms of these CVDs and to develop novel cardio-protective and therapeutic strategies to halt this dramatic development. The performance of the cardiac muscle is controlled by the spontaneous activity of pacemaker cells in the sinoatrial node (SAN) which generate the heartbeat. Importantly, the heart rate (HR) is a prognostic factor for cardiac morbidity and mortality. Our group investigates the role of HCN channels and other ion channels for the generation of a regular and well-coordinated HR. In general, pacemaking requires functional interactions between individual pacemaker cells within the SAN itself (a process called „basis entrainment”), between SAN cells and regulating neurons of the autonomic nervous system (neuronal entrainment) and finally between SAN cells and the hormone system (humoral entrainment). We hypothesize that in particular cAMP-dependent regulation of HCN4 channels contributes to the neuronal and humoral entrainment and that HCN1 and other ion channels are responsible for the “basis entrainment”, the actual synchronization process within the sinoatrial node itself (Fenske et al. Circulation 2013). We currently investigate the subtype-specific distribution of pacemaker cells in the SAN and their electrophysiological properties, aiming to relate their ion channel composition to region-specific differences in AP and rhythm generation.

As collaborators, we furthermore perform patch clamp analyses on human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to support projects that investigate diverse human cardiac diseases (e.g. Brugada syndrome, hypertrophic cardiomyopathy HCM) and the development of scalable amounts of chamber-specific CM subtypes to generate ventricular-like, atrial-like and also nodal-like bioartificial cardiac tissues (BCTs). With such approaches, we aim to understand basic mechanisms of cardiac diseases and bridge the gap to future solutions for cardiac regeneration and repair.

 

PI: PD Dr. M. Fischer, Dr. J. de la Roche

Cooperation partners: Prof. Dr. T. Kraft, Prof. Dr. I. Gruh, Prof. Dr. A. Leffler, Prof. Dr. Dr. T. Thum, Prof. Dr. C. Wahl-Schott, Dr. R. Zweigerdt

Numerous self-organized rhythms are present in the brain in distinct cortical networks, in particular in those implicated in cognitive functions. One of the most prominent synchronous signals of the mammalian brain is the theta rhythm, which is involved in packaging and segmentation of neural information. Thereby, it contributes to information processing in the brain and to the organization of cognitive processes such as learning and memory. The theta rhythm can be recorded across several brain regions and is very pronounced in the medial septum, which is composed of pacemaker neurons and there is evidence that the activity of these cells drives hippocampal theta oscillations. We are interested in understanding how HCN channels and other cation channels in these pacemaker neurons drive hippocampal theta rhythm. Moreover, we investigate other rhythms in the brain (circadian rhythm, rhythms in the thalamocortical system) and aim to understand how changes in these processes lead to epilepsy and other diseases of the central nervous system.

 

PI: Dr. H. Varbanov

Cooperation partners: Prof. Dr. C. Wahl-Schott

The family of CLC proteins comprises plasma membrane inserted chloride channels (ClC-1, ClC-2, ClC-K) and endo-lysosomal chloride/proton-exchangers (ClC-3 through ClC-7). Dysfunction of these anion transport proteins cause diverse human diseases including myotonia, aldosteronism, epilepsy, salt-wasting nephropathies with and without hearing loss, Dent’s disease or osteopetrosis. Some CLC transport proteins are regulated by their interaction with accessory subunits. The renal ClC-K channel in complex with its accessory subunit barttin contributes to resorption of sodium chloride in Henle’s loop of the kidney and to potassium secretion into the endolymph of the inner ear. Dysfunction of barttin causes Bartter syndrome type IV, a salt-wasting nephropathy with sensorineural deafness. We currently investigate the subunit stoichiometry of ClC-K/barttin complexes and unravel how posttranslational palmitoylation of barttin regulates channel physiology by affecting the channel’s gating mechanism. Precise knowledge of ClC-K/barttin interaction will help to find new strategies for development of novel diuretic drugs to treat arterial hypertension and congestive heart failure.

 

PI: PD Dr. M. Fischer, Dr. M. Grieschat

Cooperation partners: Prof. Dr. Ch. Fahlke, Prof. Dr. E. Ponimaskin

https://www.mhh.de/zentrum-physiologie/emeritus-prof-gros/forschung

 

PI: PD Dr. V. Endeward, Dr. S. Al-Samir, Prof. Dr. G. Gros