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3. Nanodomains for Excitability


targets processes such as signalling by Ca2+ channels and the ensuing Ca2+-triggered membrane fusion – the hallmarks of excitable cells. It focuses especially on voltage-gated Ca2+ channels (CaV) and ryanodine receptors (RyR, Ca2+-release channels of the endoplasmic reticulum) in sensory hair cells and atrial cardiomyocytes. We use converging bottom-up and top-down approaches to comparatively study the assembly, function and dysfunction of CaV1.3 and RyR2 and develop virus-mediated gene replacement as a therapeutic strategy targeting the presynaptic CaV1.3 channel complex. Another focus are Ferlins, multi-C2-domain proteins, that are essential for synaptic vesicle exocytosis at the presynaptic active zones of hair cells (otoferlin) and for plasma membrane resealing and T-tubule remodelling in cardiomyocytes (dysferlin). Genetic defects cause deafness (otoferlin) and cardiomyopathy (dysferlin). We will elucidate the structure and function of the molecular machineries of membrane fusion in hair cells and cardiomyocytes.
In the new RA 3.3, in addition to "neuronal plasticity", as the ability of neurons and/or synapses to adapt in response to changes in the organism's function, "cardiac plasticity" will be studied as a largely unexplored, yet very important feature of the heart.
Research Alliance 3.1: Assembly and Function of ion Channel Clusters
Research Alliance 3.2: Calcium triggered Membrane Fusion
Research Alliance 3.3: Plasticity in Heart and Brain


Research Alliance 3.1: Assembly and Function of Ion Channel Clusters

Ca2+ channels play a pivotal role in excitable cells such as neurons, sensory cells, and cardiomyocytes. In the presynaptic membrane of neurons and sensory hair cells, voltage gated Ca2+ channels (CaV channels) are the key players in synaptic transmission mediating excitation exocytosis coupling. In atrial and ventricular cardiomyocytes, excitation-contraction coupling is initiated by CaV channels that activate intracellular Ca2+-induced Ca2+-release (CICR) through ryanodine receptor (RyR2) Ca2+-release channels. Moreover, CaV channels also contribute to pacemaking in the heart and cardiac development. Both types of Ca2+ channels, CaV and RyR, form macromolecular ion channel clusters comprising tens to hundreds of channels localized in specific domains of the plasma membrane or the sarco/endoplasmic reticulum (S/ER) membrane, respectively. In RA 3.1, we address the questions, how ion channel clusters are formed and maintained, how individual channels are dynamically positioned within clusters, and how they (co)operate to generate local Ca2+signals.

Moderator

Prof. Dr. Stephan E. Lehnart
Cellular Biophysics and Translational Cardiology Section
University Medical Center Göttingen
Robert-Koch-Str. 42a
37075 Göttingen
slehnart[at]med.uni-goettingen.de


Research Groups


Research Alliance 3.2: Calcium triggered Membrane Fusion

The process of Ca2+-triggered membrane fusion is of fundamental importance in excitable cells. Neurons and neurosensory cells, such as the hair cells of the auditory pathway, rely on the Ca2+-triggered fusion of neurotransmitter-filled synaptic vesicles (SV) with the plasma membrane for synaptic signalling and information processing. Cardiomyocytes also require Ca2+-triggered vesicle fusion to release atrial natriuretic factor (ANF) and other peptide hormones from atrial cardiomyocytes, for trafficking of glucose transporters to the plasma membrane, and for resealing plasma membrane defects that arise from membrane stress during contraction and stretching.

These different fusion mechanisms likely share fundamental similarities, but their commonalities and differences are poorly known and therefore of major interest to this Research Alliance.

In sensory cells and in cardiomyocytes, the function of synaptotagmin is thought to be taken over by other C2-domain proteins, the ferlin family members (otoferlin in hair cells, dysferlin in myocytes). Otoferlin and dysferlin are major research targets as they play a role in sensorineural hearing impairment and cardiomyopathy. We focus on the elucidation of the structure and function of ferlins in vitro, we want to understand the cellular organization and function of ferlins, in comparison to synaptotagmin and eventually work towards gene replacement and gene correction by genome editing for ferlinopathies.

Moderator

Prof. Dr. Tobias Moser
Institute of Auditory Neuroscience
University Medical Center Göttingen
Robert-Koch-Str. 40
37075 Göttingen
tmoser[at]gwdg.de


Research Groups


Research Alliance 3.3: Plasticity in Heart and Brain

Neuronal plasticity has long entered the domain of public speech, being roughly defined as the capacity of the neurons and/or synapses to adjust themselves in response to alterations in the function of the organism as a whole. The neuronal adjustments serve to adapt the function of the brain to the new conditions encountered by the organism, rendering it more likely to benefit from experience, or to respond to injury.

Cardiac plasticity has been far less discussed in the literature, but is nevertheless a very important feature of the heart. We can define cardiac plasticity as “the capacity of heart cells to adjust themselves and/or their communication in response to changes of the organism”. This definition fits well with many interesting phenomena, which have their parallels in brain plasticity:

- The heart changes in response to a high degree (<1 cm2) of aortic valve stenosis (AVS), in the form of, for example, left-ventricular remodeling. Importantly, at least four classes of distinct left-ventricular clinical and proteomic phenotypes have been identified, although the patients showed the same degree of AVS. A simpler example is physiological heart remodeling in response to systematic training, which can be broadly compared with the enhancement of neuronal networks through physical training.

- Sarcomeric gene mutations that cause hypertrophic cardiomyopathy end up in strong modifications of the extracellular matrix (ECM) and cardiomyocyte disorder of the heart, which contribute to disease progression including rhythm disorders. This parallels many ECM-related brain diseases.

- Communication between cardiomyocytes, via connexin-43, is altered in heart failure patients, which increases arrhythmia risk, just as the reduction in connexin-43 levels can lead to epilepsy.

- Heart cells may undergo molecular changes to reduce potential problems, for example by downregulating Ca2+-ATPases in heart failure, perhaps to transiently prevent, but in the long-term increase episodes of arrhythmia. This type of modulation is well known in the brain.

- In advanced heart failure patients, left-ventricular assist device treatment can partly or completely reverse left-ventricular loss-of-function, leading to complete recovery in some patients. This type of treatment suggests activity-related plastic changes, of a kind that are common in the brain.

- An even more specialized example is for treatment-resistant life-threatening ventricular arrhythmia, which is profoundly reduced by radiotherapy, though Notch signaling-dependent changes in sodium channel expression. These effects parallel some of the effects of radiotherapy and Notch modulation on brain tumors.

This implies that heart plasticity is more common than most biologists may realize. At the same time, the much longer period during which brain plasticity has been investigated implies that neuroscientists possess more tools and protocols to analyze plastic changes. Applying these tools to heart systems would probably enhance our understanding of heart plasticity, far beyond the current state. This process has already started, with iPSC-derived tools, sophisticated proteomics tools and advanced imaging systems, for example, being used for both heart and brain cells.

This newly founded Line of Research 3.3 will focus on the exchange of tools and ideas on brain and heart plasticity.

Moderator

Prof. Dr. Silvio Rizzoli
Institute of Neuro- and Sensory Physiology
University Medical Center Göttingen
Robert-Koch-Str. 40
37075 Göttingen
srizzol[at]gwdg.de


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