Biology subjects

Faivre, J.-F.

Publications and source records attributed to Faivre, J.-F..

4 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↗

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↗

bioRxiv2020

Polyunsaturated phospholipids increase cell resilience to mechanical constraints

Despite the fact that PolyUnsaturated Fatty Acids (PUFA) are generally accepted to be good for health, the mechanisms of their bona fide benefits still remain elusive. PUFA are particularly enriched in the membrane Phospholipids (PLs) of selective organs, among which skeletal muscles and the cardiovascular system are prime examples. The fatty acid composition of PLs is known to regulate crucial membrane properties, including rigidity, elasticity and plasticity. Since muscle cells undergo repeated cycles of elongation and relaxation and are constantly exposed to mechanical stress, we postulated in the present study that PUFA-containing PLs could be central players for muscle cell adaptation to mechanical constraints. By a combination of in cellulo and in silico approaches, we show that PUFA, and particularly the {omega}-3 DocoHexaenoic Acid (DHA), regulate important properties of the plasma membrane that improve muscle cell resilience to mechanical constraints. Thanks to their unique property to contortionate within the bilayer plane, they facilitate the formation of Vacuole-like dilation (VLD) which, in turn, reduce membrane stress and avoid cell breakage under mechanical constraints.

cell biology↗

bioRxiv2019

A comprehensive study of Phospholipid fatty acid rearrangements in the early onset of the metabolic syndrome: correlations to organ dysfunction.

The balance within phospholipids (PL) between Saturated Fatty Acids (SFA) and mono- or poly-Unsaturated Fatty Acids (UFA), is known to regulate the biophysical properties of cellular membranes. As a consequence, perturbating this balance alters crucial cellular processes in many cell types, such as vesicular budding and the trafficking/function of membrane-anchored proteins. The worldwide spreading of the Western-diet, which is specifically enriched in saturated fats, has been clearly correlated with the emergence of a complex syndrome, known as the Metabolic Syndrome (MetS), which is defined as a cluster of risk factors for cardiovascular diseases, type 2 diabetes and hepatic steatosis. However, no clear correlations between diet-induced fatty acid redistribution within cellular PL, the severity/chronology of the symptoms associated to MetS and the function of the targeted organs, particularly in the early onset of the disease, have been established. In an attempt to fill this gap, we analyzed in the present study PL remodeling in rats exposed during 15 weeks to a High Fat/High Fructose diet (HFHF) in several organs, including known MetS targets. We show that fatty acids from the diet can distribute within PL in a very selective way, with PhosphatidylCholine being the preferred sink for this distribution. Moreover, in the HFHF rat model, most organs are protected from this redistribution, at least during the early onset of MetS, at the exception of the liver and skeletal muscles. Interestingly, such a redistribution correlates with clear-cut alterations in the function of these organs.

biochemistry↗