DE WAARD , Michel

IKr current, a major component of cardiac repolarization, is mediated by human Ether-à-go-go-Related Gene (hERG, Kv11.1) potassium channels. The blockage of these channels by pharmacological compounds is associated to drug-induced long QT syndrome (LQTS), which is a life-threatening disorder characterized by ventricular arrhythmias and defects...

Background and Purpose: Protoxin II (ProTx II) is a high affinity gating modifier that is thought to selectively block the Nav1.7 voltage-dependent Na+ channel, a major therapeutic target for the control of pain. We aimed at producing ProTx II analogues entitled with novel functionalities for cell distribution studies and biochemical...

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The goal of this study was to identify new compounds from venoms able to modulate sperm physiology and more particularly sperm motility. For this purpose, we screened the effects of 16 snake venoms cleared of molecules higher than 15 kDa on sperm motility. Venoms rich in neurotoxins like those from Oxyuranus scutellatus scutellatus or Daboia...

Aims. Coronavirus disease of 2019 (COVID-19) has rapidly become a worldwide pandemic. Many clinical trials have been initiated to fight the disease. Among those, hydroxychloroquine and azithromycin had initially been suggested to improve clinical outcomes. Despite any demonstrated beneficial effects, they are still in use in some countries but...

Two C-terminal splice variants (BI-1 and BI-2, now termed Cav2.1a and Cav2.1b) of the neuronal voltage-gated P/Q-type Ca2+channel a1A pore-forming subunit have been cloned (Mori et al., 1991, Nature, 350, 398±402). BI-1 and BI-2 code for proteins of2273 and 2424 amino acids, respectively, and differ only by their extreme carboxyl-termini...

The cytoplasmic b subunit of voltage-dependent calcium channels modulates channel properties in a subtype-specific manner and is important in channel targeting. A high affinity interaction site between the a1interaction domain (AID) in the I-II cytoplasmic loop ofa1 and the b interaction domain (BID) of the b subunit ishighly conserved among...

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The venom peptide maurocalcin (MCa) is atypical among toxins because of its ability to rapidly translocate into cells and potently activate the intracellular calcium channel type 1 ryanodine receptor (RyR1). Therefore, MCa is potentially subjected to posttranslational modifications within recipient cells. Here, we report that MCa Thr(26)...

Na v 1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened...

Different mammalian secreted phospholipases A(2) (sPLA(2) s) are expressed in male reproductive organs and/or in sperm cells but their cellular functions are still not fully characterized. Because several reports indicate a link between cellular lipids and sperm motility, we have investigated the effect of mouse group IIA, IID, IIE, V, and X...

hERG, the pore-forming subunit of the rapid component of the delayed rectifier K + current, plays a key role in ventricular repolarization. Mutations in the KCNH2 gene encoding hERG are associated with several cardiac rhythmic disorders, mainly the Long QT syndrome (LQTS) characterized by prolonged ventricular repolarization, leading to...

Inactivation of the subunit of the calcium channel in the mouse neurological mutant b4 lethargic results in a complexneurological disorder that includes absence epilepsy and ataxia. To determine the role of the calcium-channel b4-subunit gene CACNB4 on chromosome 2q22-23 in related human disorders, we screened for mutations in smallpedigrees...

Pi1 is a 35-residue toxin cross-linked by four disulfide bridges that has been isolated from the venom of thechactidae scorpion Pandinus imperator. Due to its very low abundance in the venom, we have chemicallysynthesized this toxin in order to study its biological activity. Enzyme-based proteolytic cleavage of thesynthetic Pi1 (sPi1)...

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Dear Editor, Loss-of-function and gain-of-function mutations in the KCNH2 gene cause long and short-QT syndromes (LQTS or SQTS), respectively, predisposing to life-threatening F I G U R E 1 Repolarization power of wild-type (WT) hERG as a function of temperature. A simplified and optimized action potential was applied (AP-clamp) by an automated...

Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider Cyriopagopus schmidti, has been reported to be a potent antinociceptive compound due to its action on the genetically validated NaV1.7 pain target. Using this peptide for antinociceptive applications in vivo suffers from one major drawback, namely its negative...

Abstract Photoactivatable drugs targeting ligand-gated ion channels open up new opportunities for light-guided therapeutic interventions. Photoactivable toxins targeting ion channels have the potential to control excitable cell activities with low invasiveness and high spatiotemporal precision. As proof-of-concept, we develop HwTxIV-Nvoc, a UV...

Ejaculated mammalian sperm must undergo a maturation process called capacitation before they are able to fertilize an egg. Several studies have suggested a role for members of the secreted phospholipase A2 (sPLA2) family in capacitation, acrosome reaction (AR), and fertilization, but the molecular nature of these enzymes and their specific...

Background and aims: Mutations in KCNH2 cause long or short QT syndromes (LQTS or SQTS) predisposing to life-threatening arrhythmias. Over 1000 hERG variants have been described by clinicians, but most remain to be characterised. The objective is to standardise and accelerate the phenotyping process to contribute to clinician diagnosis and...

Background and aims: Mutations in KCNH2 cause long or short QT syndromes (LQTS or SQTS) predisposing to life-threatening arrhythmias. Over 1000 hERG variants have been described by clinicians, but most remain to be characterised. The objective is to standardise and accelerate the phenotyping process to contribute to clinician diagnosis and...

Calcium current through voltage-gated calcium channels (VGCC) controls gene expression. Here, we describe a novel signalling pathway in which the VGCC Cacnb4 subunit directly couples neuronal excitability to transcription. Electrical activity induces Cacnb4 association to Ppp2r5d, a regulatory subunit of PP2A phosphatase, followed by (i)...