The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Nina D. Ullrich - One of the best experts on this subject based on the ideXlab platform.
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targeting the cardiac sodium channel to increase Excitability of stem Cell derived cardiomyocytes
Biophysical Journal, 2017Co-Authors: Valentin Sottas, Cristian Mihnea Trache, Nina D. UllrichAbstract:The cardiogenic potential of stem-Cell derived cardiomyocytes (iPSC-CM) and their prospective use for cardiac Cell therapy crucially depends on their Excitability and functional integration in myocardial tissue. Indeed, previous studies from our group have shown that Cell Excitability and interCellular coupling are strongly reduced in iPSC-CMs compared to primary cardiomyocytes. For clinical aspects, impaired Excitability and electrical signal propagation may lead to conduction slowing and the development of arrhythmia. In this project, we focus on the idea that cardiomyocyte Excitability and conduction properties are interrelated and depend on the expression of the cardiac sodium channel Nav1.5 and the major gap junction forming protein connexin-43 (Cx43). We tested the hypothesis that molecular remodeling of both proteins enhances Cell Excitability as reflected in Nav1.5 activity and action potential (AP) properties with the aim to approach native cardiomyocyte function. Using a combination of molecular modulation and electrophysiological evaluation in voltage and current clamp modes, our data demonstrate that enhanced Nav1.5 expression in iPSC-CMs significantly increased sodium current (INa in pA/pF: control 40.5±10.5, Nav1.5 118.3±27.2) and upstroke velocity (dv/dtmax, in V/s: 156±18 vs. 276±29, respectively) of the AP, a critical determinant of Cell Excitability. Typically, a fraction of iPSC-CMs also exhibited spontaneous APs with low dv/dtmax (<50 V/s) driven without Nav1.5, a hallmark of immaturity. However, after Nav1.5 overexpression, all recorded APs showed fast dv/dtmax. Furthermore, INa was also increased in Cx43-overexpressing iPSC-CMs (INa 66.2±19.8 pA/pF) suggesting that Cx43 may influence Nav1.5 expression and thereby Cell Excitability. This notion was further confirmed in immunostainings of Cx43-overexpressing iPSC-CMs demonstrating increased Nav1.5 expression at the plasma membrane, which suggests a common regulation pathway between both proteins. In conclusion, modulation of Nav1.5 and Cx43 expression greatly enhances the Excitability of iPSC-CMs and may represent a powerful new target for improving the functional maturation of iPSC-CMs.
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Targeting the Cardiac Sodium Channel to Increase Excitability of Stem-Cell Derived Cardiomyocytes
Biophysical Journal, 2017Co-Authors: Valentin Sottas, Cristian Mihnea Trache, Nina D. UllrichAbstract:The cardiogenic potential of stem-Cell derived cardiomyocytes (iPSC-CM) and their prospective use for cardiac Cell therapy crucially depends on their Excitability and functional integration in myocardial tissue. Indeed, previous studies from our group have shown that Cell Excitability and interCellular coupling are strongly reduced in iPSC-CMs compared to primary cardiomyocytes. For clinical aspects, impaired Excitability and electrical signal propagation may lead to conduction slowing and the development of arrhythmia. In this project, we focus on the idea that cardiomyocyte Excitability and conduction properties are interrelated and depend on the expression of the cardiac sodium channel Nav1.5 and the major gap junction forming protein connexin-43 (Cx43). We tested the hypothesis that molecular remodeling of both proteins enhances Cell Excitability as reflected in Nav1.5 activity and action potential (AP) properties with the aim to approach native cardiomyocyte function. Using a combination of molecular modulation and electrophysiological evaluation in voltage and current clamp modes, our data demonstrate that enhanced Nav1.5 expression in iPSC-CMs significantly increased sodium current (INa in pA/pF: control 40.5±10.5, Nav1.5 118.3±27.2) and upstroke velocity (dv/dtmax, in V/s: 156±18 vs. 276±29, respectively) of the AP, a critical determinant of Cell Excitability. Typically, a fraction of iPSC-CMs also exhibited spontaneous APs with low dv/dtmax (
Valentin Sottas - One of the best experts on this subject based on the ideXlab platform.
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targeting the cardiac sodium channel to increase Excitability of stem Cell derived cardiomyocytes
Biophysical Journal, 2017Co-Authors: Valentin Sottas, Cristian Mihnea Trache, Nina D. UllrichAbstract:The cardiogenic potential of stem-Cell derived cardiomyocytes (iPSC-CM) and their prospective use for cardiac Cell therapy crucially depends on their Excitability and functional integration in myocardial tissue. Indeed, previous studies from our group have shown that Cell Excitability and interCellular coupling are strongly reduced in iPSC-CMs compared to primary cardiomyocytes. For clinical aspects, impaired Excitability and electrical signal propagation may lead to conduction slowing and the development of arrhythmia. In this project, we focus on the idea that cardiomyocyte Excitability and conduction properties are interrelated and depend on the expression of the cardiac sodium channel Nav1.5 and the major gap junction forming protein connexin-43 (Cx43). We tested the hypothesis that molecular remodeling of both proteins enhances Cell Excitability as reflected in Nav1.5 activity and action potential (AP) properties with the aim to approach native cardiomyocyte function. Using a combination of molecular modulation and electrophysiological evaluation in voltage and current clamp modes, our data demonstrate that enhanced Nav1.5 expression in iPSC-CMs significantly increased sodium current (INa in pA/pF: control 40.5±10.5, Nav1.5 118.3±27.2) and upstroke velocity (dv/dtmax, in V/s: 156±18 vs. 276±29, respectively) of the AP, a critical determinant of Cell Excitability. Typically, a fraction of iPSC-CMs also exhibited spontaneous APs with low dv/dtmax (<50 V/s) driven without Nav1.5, a hallmark of immaturity. However, after Nav1.5 overexpression, all recorded APs showed fast dv/dtmax. Furthermore, INa was also increased in Cx43-overexpressing iPSC-CMs (INa 66.2±19.8 pA/pF) suggesting that Cx43 may influence Nav1.5 expression and thereby Cell Excitability. This notion was further confirmed in immunostainings of Cx43-overexpressing iPSC-CMs demonstrating increased Nav1.5 expression at the plasma membrane, which suggests a common regulation pathway between both proteins. In conclusion, modulation of Nav1.5 and Cx43 expression greatly enhances the Excitability of iPSC-CMs and may represent a powerful new target for improving the functional maturation of iPSC-CMs.
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Targeting the Cardiac Sodium Channel to Increase Excitability of Stem-Cell Derived Cardiomyocytes
Biophysical Journal, 2017Co-Authors: Valentin Sottas, Cristian Mihnea Trache, Nina D. UllrichAbstract:The cardiogenic potential of stem-Cell derived cardiomyocytes (iPSC-CM) and their prospective use for cardiac Cell therapy crucially depends on their Excitability and functional integration in myocardial tissue. Indeed, previous studies from our group have shown that Cell Excitability and interCellular coupling are strongly reduced in iPSC-CMs compared to primary cardiomyocytes. For clinical aspects, impaired Excitability and electrical signal propagation may lead to conduction slowing and the development of arrhythmia. In this project, we focus on the idea that cardiomyocyte Excitability and conduction properties are interrelated and depend on the expression of the cardiac sodium channel Nav1.5 and the major gap junction forming protein connexin-43 (Cx43). We tested the hypothesis that molecular remodeling of both proteins enhances Cell Excitability as reflected in Nav1.5 activity and action potential (AP) properties with the aim to approach native cardiomyocyte function. Using a combination of molecular modulation and electrophysiological evaluation in voltage and current clamp modes, our data demonstrate that enhanced Nav1.5 expression in iPSC-CMs significantly increased sodium current (INa in pA/pF: control 40.5±10.5, Nav1.5 118.3±27.2) and upstroke velocity (dv/dtmax, in V/s: 156±18 vs. 276±29, respectively) of the AP, a critical determinant of Cell Excitability. Typically, a fraction of iPSC-CMs also exhibited spontaneous APs with low dv/dtmax (
Emilio Carbone - One of the best experts on this subject based on the ideXlab platform.
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calcium channel types contributing to chromaffin Cell Excitability exocytosis and endocytosis
Cell Calcium, 2012Co-Authors: Satyajit Mahapatra, Chiara Calorio, David H F Vandael, Andrea Marcantoni, Valentina Carabelli, Emilio CarboneAbstract:Voltage gated Ca2+ channels are effective voltage sensors of plasma membrane which convert Cell depolarizations into Ca2+ signaling. The chromaffin Cells of the adrenal medulla utilize a large number of Ca2+ channel types to drive the Ca2+-dependent release of catecholamines into blood circulation, during normal or stress-induced conditions. Some of the Ca2+ channels expressed in chromaffin Cells (L, N, P/Q, R and T), however, do not control only vesicle fusion and catecholamine release. They also subserve a variety of key activities which are vital for the physiological and pathological functioning of the Cell, like: (i) shaping the action potentials of electrical oscillations driven either spontaneously or by ACh stimulation, (ii) controlling the action potential frequency of tonic or bursts firing, (iii) regulating the compensatory and excess endocytosis following robust exocytosis and (iv) driving the remodeling of Ca2+ signaling which occurs during stressors stimulation. Here, we will briefly review the well-established properties of voltage-gated Ca2+ channels accumulated over the past three decades focusing on the most recent discoveries on the role that L- (Cav1.2, Cav1.3) and T-type (Cav3.2) channels play in the control of Excitability, exocytosis and endocytosis of chromaffin Cells in normal and stress-mimicking conditions
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Ca_v1.3 and BK Channels for Timing and Regulating Cell Firing
Molecular Neurobiology, 2010Co-Authors: David Henry Vandael, Satyajit Mahapatra, Andrea Marcantoni, Anton Caro, Peter Ruth, Annalisa Zuccotti, Marlies Knipper, Emilio CarboneAbstract:L-type Ca^2+ channels (LTCCs, Ca_v1) open readily during membrane depolarization and allow Ca^2+ to enter the Cell. In this way, LTCCs regulate Cell Excitability and trigger a variety of Ca^2+-dependent physiological processes such as: excitation–contraction coupling in muscle Cells, gene expression, synaptic plasticity, neuronal differentiation, hormone secretion, and pacemaker activity in heart, neurons, and endocrine Cells. Among the two major isoforms of LTCCs expressed in excitable tissues (Ca_v1.2 and Ca_v1.3), Ca_v1.3 appears suitable for supporting a pacemaker current in spontaneously firing Cells. It has steep voltage dependence and low threshold of activation and inactivates slowly. Using Ca_v1.3^−/− KO mice and membrane current recording techniques such as the dynamic and the action potential clamp, it has been possible to resolve the time course of Ca_v1.3 pacemaker currents that regulate the spontaneous firing of dopaminergic neurons and adrenal chromaffin Cells. In several Cell types, Ca_v1.3 is selectively coupled to BK channels within membrane nanodomains and controls both the firing frequency and the action potential repolarization phase. Here we review the most critical aspects of Ca_v1.3 channel gating and its coupling to large conductance BK channels recently discovered in spontaneously firing neurons and neuroendocrine Cells with the aim of furnishing a converging view of the role that these two channel types play in the regulation of Cell Excitability.
Cristian Mihnea Trache - One of the best experts on this subject based on the ideXlab platform.
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targeting the cardiac sodium channel to increase Excitability of stem Cell derived cardiomyocytes
Biophysical Journal, 2017Co-Authors: Valentin Sottas, Cristian Mihnea Trache, Nina D. UllrichAbstract:The cardiogenic potential of stem-Cell derived cardiomyocytes (iPSC-CM) and their prospective use for cardiac Cell therapy crucially depends on their Excitability and functional integration in myocardial tissue. Indeed, previous studies from our group have shown that Cell Excitability and interCellular coupling are strongly reduced in iPSC-CMs compared to primary cardiomyocytes. For clinical aspects, impaired Excitability and electrical signal propagation may lead to conduction slowing and the development of arrhythmia. In this project, we focus on the idea that cardiomyocyte Excitability and conduction properties are interrelated and depend on the expression of the cardiac sodium channel Nav1.5 and the major gap junction forming protein connexin-43 (Cx43). We tested the hypothesis that molecular remodeling of both proteins enhances Cell Excitability as reflected in Nav1.5 activity and action potential (AP) properties with the aim to approach native cardiomyocyte function. Using a combination of molecular modulation and electrophysiological evaluation in voltage and current clamp modes, our data demonstrate that enhanced Nav1.5 expression in iPSC-CMs significantly increased sodium current (INa in pA/pF: control 40.5±10.5, Nav1.5 118.3±27.2) and upstroke velocity (dv/dtmax, in V/s: 156±18 vs. 276±29, respectively) of the AP, a critical determinant of Cell Excitability. Typically, a fraction of iPSC-CMs also exhibited spontaneous APs with low dv/dtmax (<50 V/s) driven without Nav1.5, a hallmark of immaturity. However, after Nav1.5 overexpression, all recorded APs showed fast dv/dtmax. Furthermore, INa was also increased in Cx43-overexpressing iPSC-CMs (INa 66.2±19.8 pA/pF) suggesting that Cx43 may influence Nav1.5 expression and thereby Cell Excitability. This notion was further confirmed in immunostainings of Cx43-overexpressing iPSC-CMs demonstrating increased Nav1.5 expression at the plasma membrane, which suggests a common regulation pathway between both proteins. In conclusion, modulation of Nav1.5 and Cx43 expression greatly enhances the Excitability of iPSC-CMs and may represent a powerful new target for improving the functional maturation of iPSC-CMs.
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Targeting the Cardiac Sodium Channel to Increase Excitability of Stem-Cell Derived Cardiomyocytes
Biophysical Journal, 2017Co-Authors: Valentin Sottas, Cristian Mihnea Trache, Nina D. UllrichAbstract:The cardiogenic potential of stem-Cell derived cardiomyocytes (iPSC-CM) and their prospective use for cardiac Cell therapy crucially depends on their Excitability and functional integration in myocardial tissue. Indeed, previous studies from our group have shown that Cell Excitability and interCellular coupling are strongly reduced in iPSC-CMs compared to primary cardiomyocytes. For clinical aspects, impaired Excitability and electrical signal propagation may lead to conduction slowing and the development of arrhythmia. In this project, we focus on the idea that cardiomyocyte Excitability and conduction properties are interrelated and depend on the expression of the cardiac sodium channel Nav1.5 and the major gap junction forming protein connexin-43 (Cx43). We tested the hypothesis that molecular remodeling of both proteins enhances Cell Excitability as reflected in Nav1.5 activity and action potential (AP) properties with the aim to approach native cardiomyocyte function. Using a combination of molecular modulation and electrophysiological evaluation in voltage and current clamp modes, our data demonstrate that enhanced Nav1.5 expression in iPSC-CMs significantly increased sodium current (INa in pA/pF: control 40.5±10.5, Nav1.5 118.3±27.2) and upstroke velocity (dv/dtmax, in V/s: 156±18 vs. 276±29, respectively) of the AP, a critical determinant of Cell Excitability. Typically, a fraction of iPSC-CMs also exhibited spontaneous APs with low dv/dtmax (
Peter Jedlicka - One of the best experts on this subject based on the ideXlab platform.
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Lack of β-amyloid Cleaving enzyme-1 (BACE1) Impairs Long-Term Synaptic Plasticity but Enhances Granule Cell Excitability and Oscillatory Activity in the Dentate Gyrus in Vivo
Brain structure & function, 2019Co-Authors: Matej Vnencak, Marieke L. Schölvinck, Stephan W. Schwarzacher, Thomas Deller, Michael Willem, Peter JedlickaAbstract:BACE1 is a β-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer’s disease (AD). The entorhinal cortex and the dentate gyrus are important for learning and memory, which are affected in the early stages of AD. Since BACE1 is a potential target for AD therapy, it is crucial to understand its physiological role in these brain regions. Here, we examined the function of BACE1 in the dentate gyrus. We show that loss of BACE1 in the dentate gyrus leads to increased granule Cell Excitability, indicated by enhanced efficiency of synaptic potentials to generate granule Cell spikes. The increase in granule Cell Excitability was accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path. In summary, this is the first detailed electrophysiological study of BACE1 deletion at the network level in vivo. The results suggest that BACE1 is important for normal dentate gyrus network function. This has implications for the use of BACE1 inhibitors as therapeutics for AD therapy, since BACE1 inhibition could similarly disrupt synaptic plasticity and Excitability in the entorhinal–dentate circuitry.
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Impairment of in vivo theta‐burst long‐term potentiation and network Excitability in the dentate gyrus of synaptopodin‐deficient mice lacking the spine apparatus and the cisternal organelle
Hippocampus, 2009Co-Authors: Peter Jedlicka, Stephan W. Schwarzacher, Raphael Winkels, Friederike Kienzler, Michael Frotscher, Clive R. Bramham, Christian Schultz, Carlos Bas Orth, Thomas DellerAbstract:The function of the spine apparatus in dendritic spines and the cisternal organelles in axon initial segments is little understood. The actin-associated protein, synaptopodin, is essential for the formation of these organelles which are absent in synaptopodin 2/2 mice. Here, we used synaptopodin 2/2 mice to explore the role of the spine appa- ratus and the cisternal organelle in synaptic plasticity and local circuit Excitability in response to activation of the perforant path input to the dentate gyrus in vivo. We found impaired long-term potentiation follow- ing theta-burst stimulation, whereas tetanus-evoked LTP was unaffected. Furthermore, paired-pulse inhibition of the population spike was reduced and granule Cell Excitability was enhanced in mutants, hence revealing an impairment of local network inhibition. In summary, our data represent the first electrophysiological evidence that the lack of the spine apparatus and the cisternal organelle leads to a defect in long- term synaptic plasticity and alterations in local circuit control of granule Cell Excitability under adult in vivo conditions. V C 2008 Wiley-Liss, Inc.