Biology subjects

Chatelier, A.

Publications and source records attributed to Chatelier, A..

6 recordsLinked to original sources

bioRxiv2026

Nav1.5 regulates intrinsic cardiac neuronal excitability and expands the cellular basis of SCN5A channelopathies

Background: Loss- and gain-of-function variants in SCN5A, encoding the cardiac sodium channel Nav1.5, are major causes of inherited cardiac channelopathies. Their pathophysiology has almost exclusively been attributed to altered cardiomyocyte excitability and cardiac conduction. However, growing evidence indicates that autonomic dysfunction contributes to these disorders, raising the possibility that Nav1.5 dysfunction may also affect the intrinsic cardiac nervous system. Objectives: We investigated whether Nav1.5 is functionally expressed in murine intrinsic cardiac neurons and evaluated its contribution to neuronal excitability. Methods: Scn5a expression was investigated by digital PCR and immunocytochemistry in isolated murine intracardiac neurons. Whole-cell patch-clamp recordings were used to characterize sodium currents and action potential properties in wild-type and Scn5a+/- mice. Results: Scn5a transcripts and Nav1.5 protein were detected in intrinsic cardiac neurons. Voltage-clamp recordings identified a tetrodotoxin-resistant sodium current accounting for approximately 8% of the total sodium current and displaying pharmacological and biophysical properties consistent with Nav1.5. Activation and inactivation analyses indicated that Nav1.5 is the predominant sodium conductance available at most polarized membrane potentials. Accordingly, Scn5a haploinsufficiency selectively altered action potential threshold, maximal upstroke velocity, overshoot and duration in neurons resting below -60 mV, whereas more depolarized neurons were essentially unaffected. No structural or neurochemical remodeling of intrinsic cardiac ganglia was detected. Conclusion: Nav1.5 is a functional determinant of intrinsic cardiac neuronal excitability. These findings identify the intrinsic cardiac nervous system as a new cellular target of SCN5A dysfunction and suggest that inherited cardiac sodium channelopathies could involve alterations in both myocardial and intrinsic neuronal electrophysiology.

physiology↗

bioRxiv2025

Endothelin Signaling via EDNRB receptor Reduces Proliferation and Promotes Proneural-to-Mesenchymal Transition in Gliomas

Diffuse gliomas are incurable primary brain tumors encompassing three histo-molecular subtypes: glioblastomas (GB), astrocytomas, and oligodendrogliomas. The latter two harbor IDH1 mutations and exhibit slower progression than glioblastomas. Diffuse gliomas are composed of highly plastic tumor cells capable of transitioning between astrocyte-like, oligodendrocyte-like, progenitor-like, and mesenchymal-like states, driven by genetic alterations and microenvironmental cues. The proneural-to-mesenchymal transition (PMT), associated with increased malignancy, is notably influenced by cytokines in the tumor microenvironment. Endothelin cytokines (ET-1, ET-2, ET-3), primarily secreted by vascular cells, regulate not only vascular tone but also astrocyte and neural stem cell proliferation via the G-protein-coupled receptors EDNRA and EDNRB. Prior studies using serum-cultured glioma lines suggested pro-proliferative effects of endothelins; however, such models poorly recapitulate the in vivo glioma context. In this study, we comprehensively revisited endothelin signaling - covering receptor expression, regulation, downstream pathways, and cellular responses-using eleven serum-free, patient-derived glioma lines (glioblastomas, IDH-wt and IDH-mutant oligodendrogliomas and astrocytomas), along with primary tumor samples. Multi-omics and electrophysiological analyses revealed EDNRB as the predominant receptor, enriched in astrocyte-like cells, upregulated by BMPs or growth factor withdrawal, and downregulated by interferons, IL-6 cytokines, endothelins, and Hippo/YAP activation. In contrast, EDNRA was expressed by a perivascular tumor subpopulation and induced by Notch signaling in glioblastomas but not in IDH1-mutant cells. Functionally, endothelins reduced proliferation across all models while promoting migration and PMT. Mechanistically, EDNRB activation increased intracellular Ca{superscript 2} and activated ERK, STAT3, and apamin-sensitive SK2/SK3 potassium channels. These findings identify endothelin signaling as an important regulator of glioma cell plasticity and behavior. HighlightsO_LIEDNRB is the predominant endothelin receptor expressed in glioma cells, with a small subset of tumor cells expressing EDNRA in close proximity to blood vessels C_LIO_LIEndothelin signaling reduces proliferation while promoting cell migration and Proneural-to-Mesenchymal transition C_LIO_LIEndothelin activates downstream Ca2+, K+, ERK, and STAT3 signaling pathways C_LIO_LIEDNRB expression is both positively and negatively regulated by inflammatory cytokines and the Hippo/YAP1 pathway, whereas EDNRA is upregulated by Notch signaling and hypoxia C_LI

cancer biology↗

bioRxiv2024

Distinct Excitability Properties of Cardiac Calbindin Neurons: Identifying a Unique Neuronal Population

The intrinsic cardiac nervous system is a complex system that plays a critical role in the regulation of cardiac physiological parameters and has been shown to contribute to cardiac arrhythmias. To date, several types of neurons with distinct neurochemical and electrophysiological phenotypes have been identified. However, no study has correlated the neurochemical phenotype to a specific electrophysiological behavior. Calbindin-D28k, a calcium binding protein, is expressed in numerous cardiac neurons. Given that changes in neuronal excitability have been associated with arrhythmia susceptibility and that calbindin expression has been associated with modulations of neuronal excitability, our objective is to assess whether the cardiac calbindin neuronal population has specific properties that could be involved in cardiac modulation and arrhythmias. By using a Cre-Lox mouse model to specifically target calbindin neurons with a fluorescent reporter, we characterized the neurochemical and the electrophysiological phenotype of this cardiac neuronal population. Calbindin neurons exhibit a specific neurochemical profile and a larger soma with shorter neurite length compared to other neurons. This was combined with a distinct electrophysiological signature characterized by a lower excitability with a predominantly phasic profile associated to a lower N-type calcium current density. These properties resemble to the cardiac neuronal remodeling observed in pathologies such as type II diabetes and heart failure. Therefore, we believe that this specific neuronal population deserves investigations in the context of these pathologies.

physiology↗

bioRxiv2024

DMD Human iPSC-derived skeletal muscle cells recapitulate selective calcium dysregulation pathways.

This study investigates the functional characteristics of induced pluripotent stem cell-derived muscle cells (hiPSC-skMCs) from Duchenne muscular dystrophy (DMD) patients, focusing on their regulation of intracellular calcium concentration. DMD, a progressive muscle degenerative disease, arises from mutations in the dystrophin gene and is characterized by elevated intracellular calcium levels, exacerbating disease progression. This work highlights that DMD hiPSC-skMCs demonstrate unique calcium signatures with increased intracellular calcium compared to healthy counterparts. These cells also exhibit both heightened calcium response when stimulated by electrical fields or acetylcholine and more pronounced constitutive calcium entries. While RNAseq data from these cells reaffirmed known dysregulation mechanisms seen in other dystrophin-deficient models, certain pathways like purinergic or store-operated calcium entries did not show disruption in this DMD model. This discrepancy suggests that not all mechanisms observed in animal models may be equally relevant in human cases, pointing towards specific molecular targets that could be more effective for DMD treatment strategies.

cell biology↗

bioRxiv2021

Molecular and functional characterization of the mouse intracardiac nervous system

BackgroundThe intracardiac nervous system (ICNS) refers to clusters of neurons, located within the heart, which participate to the neuronal regulation of cardiac functions and which are involved in the initiation of cardiac arrhythmias. Therefore, deciphering its role in cardiac physiology and physiopathology is mandatory. ObjectiveThe aim of this study is to provide a phenotypic, electrophysiological and pharmacological characterization of the mouse ICNS, which is still poorly characterized. MethodsGlobal cardiac innervation and phenotypic diversity were investigated using immunohistochemistry on cleared murine heart and on tissue sections. Patch clamp technique was used for electrophysiological and pharmacological characterization of isolated mouse intracardiac neurons. ResultsWe have identified the expression of seven distinct neuronal markers within mouse ICNS, thus proving the neurochemical diversity of this network. Of note, it was the first time that the existence of neurons expressing the calcium binding protein calbindin, the neuropeptide Y (NPY) and the cocain and amphetamine regulated transcript (CART) peptide, was described in the mouse. Electrophysiological studies also revealed the existence of four different neuronal populations based on their electrical behavior. Finally, we showed that these neurons can be modulated by several neuromodulators. ConclusionThis study showed that mouse ICNS presents a molecular and functional complexity similar to other species, and is therefore a suitable model to decipher the role of individual neuronal subtypes regarding the modulation of cardiac function and the initiation of cardiac arrhythmias.

physiology↗

bioRxiv2020

Fine tuning of calcium constitutive entry by optogenetically-controlled membrane polarization: impact on cell migration.

Anomalies in constitutive calcium entry (CCE) have been commonly attributed to cell dysfunction in pathological conditions such as cancer. Calcium influxes of this type rely on channels, such as TRP, to be constitutively opened and strongly depend on membrane potential and calcium driving force. We developed an optogenetic approach based on expression of the halorhodopsin chloride pump to study CCE in non-excitable cells. Using C2C12 cells, we found that halorhodopsin can be used to achieve a finely-tuned control of membrane polarization. Escalating the membrane polarization by incremental changes in light led to a concomitant increase in CCE through TRPV2 channels. Moreover, light-induced calcium entry through TRPV2 channels promoted cell migration. Our study shows for the first time that by modulating CCE and related physiological responses such as cell motility, halorhodopsin serves as a potentially powerful tool that could open new avenues for the study of CCE and associated cellular behaviors.

cell biology↗