The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND.

Purpose: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND.

Structural basis for human Ca3.2 inhibition by selective antagonists.

The Ca3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Ca3.

New insights into the physiology and pathophysiology of the atypical sodium leak channel NALCN.

Cell excitability and its modulation by hormones and neurotransmitters involve the concerted action of a large repertoire of membrane proteins, especially ion channels. Unique complements of coexpressed ion channels are exquisitely balanced against each other in different excitable cell types, establishing distinct electrical properties that are tailored for diverse physiological contributions, and dysfunction of any component may induce a disease state. A crucial parameter controlling cell excitability is the resting membrane potential (RMP) set by extra- and intracellular concentrations of ions, mainly Na, K, and Cl, and their passive permeation across the cell membrane through leak ion channels.

Safety profile of the lopinavir/ritonavir combination before and during the SARS-CoV-2 pandemic.

Introduction: When the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic began, there were no effective treatments assessed by clinical trials. In this context, in France, the French Public Health Council issued, from 5 March, 2020, several proposed recommendations for the therapeutic management of this new disease. This included the use of combination lopinavir/ritonavir, which is usually indicated as HIV treatment.

Comparative study of the adverse event profile of hydroxychloroquine before and during the Sars-CoV2 pandemic.

Aims: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there were no clinically-tested medications for the effective treatment of coronavirus disease. In this context, on 5 March 2020, the French Public Health Council issued several recommendations for the therapeutic management of this new disease, including the use of hydroxychloroquine (HCQ). An unexpected cardiovascular safety signal was quickly identified as being more frequent than expected thanks to the reports of adverse drug reactions (ADRs) submitted to French regional pharmacovigilance centres (RPVC).

New Challenges Resulting From the Loss of Function of Na1.4 in Neuromuscular Diseases.

The voltage-gated sodium channel Na1.4 is a major actor in the excitability of skeletal myofibers, driving the muscle force in response to nerve stimulation. Supporting further this key role, mutations in , the gene encoding the pore-forming α subunit of Na1.

Sodium background currents in endocrine/neuroendocrine cells: Towards unraveling channel identity and contribution in hormone secretion.

In endocrine/neuroendocrine tissues, excitability of secretory cells is patterned by the repertoire of ion channels and there is clear evidence that extracellular sodium (Na) ions contribute to hormone secretion. While voltage-gated channels involved in action potential generation are well-described, the background 'leak' channels operating near the resting membrane potential are much less known, and in particular the channels supporting a background entry of Na ions. These background Na currents (called here 'I') have the ability to modulate the resting membrane potential and subsequently affect action potential firing.

Trastuzumab-emtansine induced pleural and pericardial effusions.

Introduction: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate which combine trastuzumab (T), a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER2), and a cytotoxic molecule derived from maytansine (DM1).

Case Report: We report the first case of T-DM1-associated pleural and pericardial effusions three weeks after the second course of T-DM1 in a patient with breast cancer. Drug-induced pleural and pericardial effusions was implicated in the absence of other etiologies.

The sodium leak channel NALCN regulates cell excitability of pituitary endocrine cells.

Anterior pituitary endocrine cells that release hormones such as growth hormone and prolactin are excitable and fire action potentials. In these cells, several studies previously showed that extracellular sodium (Na ) removal resulted in a negative shift of the resting membrane potential (RMP) and a subsequent inhibition of the spontaneous firing of action potentials, suggesting the contribution of a Na background conductance. Here, we show that the Na leak channel NALCN conducts a Ca - Gd -sensitive and TTX-resistant Na background conductance in the GH cell line, a cell model of pituitary endocrine cells.

A sodium background conductance controls the spiking pattern of mouse adrenal chromaffin cells in situ.

Key Points: Mouse chromaffin cells in acute adrenal slices exhibit two distinct spiking patterns, a repetitive mode and a bursting mode. A sodium background conductance operates at rest as demonstrated by the membrane hyperpolarization evoked by a low Na -containing extracellular saline. This sodium background current is insensitive to TTX, is not blocked by Cs ions and displays a linear I-V relationship at potentials close to chromaffin cell resting potential.

Neuronal Cav3 channelopathies: recent progress and perspectives.

T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knock-out mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases.

A novel phospho-modulatory mechanism contributes to the calcium-dependent regulation of T-type Ca channels.

Ca3 / T-type Ca channels are dynamically regulated by intracellular Ca ions, which inhibit Ca3 availability. Here, we demonstrate that this inhibition becomes irreversible in the presence of non-hydrolysable ATP analogs, resulting in a strong hyperpolarizing shift in the steady-state inactivation of the residual Ca3 current. Importantly, the effect of these ATP analogs was prevented in the presence of intracellular BAPTA.

Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties.

The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium channel NALCN plays a crucial role in the maintenance of the resting membrane potential. Importantly, NALCN mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) and congenital contractures of limbs and face, hypotonia and developmental delay (CLIFAHDD), which are recessively and dominantly inherited, respectively.

Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neurons.

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by deficient β-glucuronidase (β-gluc) activity. Significantly reduced β-gluc activity leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. Numerous combinations of mutations in GUSB (the gene that codes for β-gluc) cause a range of neurological features that make disease prognosis and treatment challenging.

De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene.

Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy.

Modulation of T-type Ca2+ channels by Lavender and Rosemary extracts.

Medicinal plants represent a significant reservoir of unexplored substances for early-stage drug discovery. Of interest, two flowering Mediterranean plants have been used for thousands of years for their beneficial effects on nervous disorders, including anxiety and mood. However, the therapeutic potential of these plants regarding their ability to target ion channels and neuronal excitability remains largely unknown.

Characterization of a dengue NS4B inhibitor originating from an HCV small molecule library.

Dengue is the most important mosquito-transmitted viral disease and a major global health concern. Over the last decade, dengue virus (DENV) drug discovery and development has intensified, however, this has not resulted in approved DENV-specific antiviral treatments yet. DENV and hepatitis C virus (HCV) belong to the same Flaviviridae family and, in contrast to DENV, antiviral treatments for HCV have been licensed.

Direct measurement of individual phonon lifetimes in the clathrate compound BaGeAu.

Engineering lattice thermal conductivity requires to control the heat carried by atomic vibration waves, the phonons. The key parameter for quantifying it is the phonon lifetime, limiting the travelling distance, whose determination is however at the limits of instrumental capabilities. Here, we show the achievement of a direct quantitative measurement of phonon lifetimes in a single crystal of the clathrate BaGeAu, renowned for its puzzling 'glass-like' thermal conductivity.

Characterization of the dominant inheritance mechanism of Episodic Ataxia type 2.

Episodic Ataxia type 2 (EA2) is an autosomal dominant neuronal disorder linked to mutations in the Ca2.1 subunit of P/Q-type calcium channels. In vitro studies have established that EA2 mutations induce loss of channel activity and that EA2 mutants can exert a dominant negative effect, suppressing normal Ca2.

T-type voltage gated calcium channels are involved in endothelium-dependent relaxation of mice pulmonary artery.

In pulmonary arterial endothelial cells, Ca channels and intracellular Ca concentration ([Ca]) control the release of vasorelaxant factors such as nitric oxide and are involved in the regulation of pulmonary arterial blood pressure. The present study was undertaken to investigate the implication of T-type voltage-gated Ca channels (T-VGCCs, Ca3.1 channel) in the endothelium-dependent relaxation of intrapulmonary arteries.

Activity-dependent regulation of T-type calcium channels by submembrane calcium ions.

Voltage-gated Ca channels are involved in numerous physiological functions and various mechanisms finely tune their activity, including the Ca ion itself. This is well exemplified by the Ca-dependent inactivation of L-type Ca channels, whose alteration contributes to the dramatic disease Timothy Syndrome. For T-type Ca channels, a long-held view is that they are not regulated by intracellular Ca.

CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism.

Primary aldosteronism (PA) is the most common form of secondary hypertension. Mutations in KCNJ5, ATP1A1, ATP2B3 and CACNA1D are found in aldosterone producing adenoma (APA) and familial hyperaldosteronism (FH). A recurrent mutation in CACNA1H (coding for Cav3.

Genetic alteration of the metal/redox modulation of Cav3.2 T-type calcium channel reveals its role in neuronal excitability.

Key Points: In this study, we describe a new knock-in (KI) mouse model that allows the study of the H191-dependent regulation of T-type Cav3.2 channels. Sensitivity to zinc, nickel and ascorbate of native Cav3.