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The Thr226Met pathologic variant of the SCN1A gene has been associated with the clinical development of an early infantile developmental and epileptic encephalopathy (EIDEE) different from Dravet's syndrome. The electrophysiological mechanisms of the mutated channel lead to a paradoxical gain and loss of function. The use of sodium channel blockers (SCB) that counteract this gain of function has been described in previous studies and they can be safely administered to patients carrying mutations in other sodium channel subtypes without causing a worsening of seizures. We report the use of SCB in a child harboring the Thr226Met pathologic variant of SCN1A with early-onset pharmaco-resistant migrating seizures, as well as developmental delay. Lacosamide led to a dramatic reduction in seizure frequency; however, only a mild improvement in the epileptic activity depicted by electroencephalography (EEG) was achieved. The introduction of carbamazepine as an add-on therapy led to a notable reduction in epileptic activity via EEG and to an improvement in sensorimotor development. Despite the overall clinical improvement, the patient developed febrile seizures and a nonepileptic jerking of the right hand. In this case of EIDEE with the Thr226Met variant, we demonstrate a beneficial pharmacological intervention of SCB in contrast to findings described in current literature. Our report encourages the cautious use of SCB at early stages of the disease in patients carrying this pathologic variant. [ABSTRACT FROM AUTHOR]

BACKGROUND Pyrethroids are the most widely used insecticides for the control of malaria transmitting Anopheles gambiae mosquitoes and rapid increase in resistance to this insecticide class is of major concern. Pyrethroids target the Voltage Gated Sodium Channels (VGSCs), that have a key role in the normal function of the mosquitoes' nervous system. VGSC mutations L995F and L995S have long been associated with pyrethroid resistance and screening for their presence is routine in insecticide resistance management programs. Recently, a VGSC haplotype containing two amino acid substitutions associated with resistance in other species, V402L and I1527T, was identified. These two VGSC mutations are found in tight linkage and are mutually exclusive to the classical L995F/S mutations. RESULTS: We identify the presence of the V402L‐I1527T haplotype in resistant An. coluzzii colonized strains and in field populations from Burkina Faso, at frequencies higher than previously reported; in some cases almost reaching fixation. Functional validation of V402L in insecticide resistance using a CRISPR/Cas9 genome modified line showed that it confers reduced mortality after exposure to all tested pyrethroids and DDT, but at lower levels compared to L995F. In contrast to L995F however, no fitness costs were identified for mosquitoes carrying V402L under laboratory conditions. CONCLUSION: The V402L substitution confers pyrethroid resistance in An. gambiae in the absence of any other VGSC substitution and/or alternative resistance mechanisms. The lower fitness cost associated with this kdr mutation may provide a selective advantage over the classical kdr in some settings and genotyping at this locus should be added in the list of resistant alleles for routine screening. [ABSTRACT FROM AUTHOR]

Modification of voltage‐gated Na+ channel (NaV) function by intracellular Ca2+ has been a topic of much controversy. Early studies relied on measuring NaV function in the absence or presence of intracellular Ca2+, and generated seemingly disparate results. Subsequent investigations revealed the mechanism(s) of Ca2+‐driven NaV modulation are complex and involve multiple accessory proteins. The Ca2+‐sensing protein calmodulin (CaM) has a central role in tuning NaV function to [Ca2+]i, but the mechanism has been obscured by other proteins (such as fibroblast growth factors (FGF) or CaM‐dependent kinase II (CaMKII)) that can also modify channel function or exert an influence in a Ca2+‐dependent manner. Significant progress has been made in understanding the architecture of full‐length ion channels and the structural and biophysical details of NaV–accessory protein interactions. Interdisciplinary structure–function studies are beginning to resolve the effect each interaction has on NaV gating. Carefully designed structure‐guided or strategically selected disease‐associated mutations are able to impair NaV–accessory protein interactions without altering other properties of channel function. Recently CaM was found to engage part of NaV1.5 that is required for channel inactivation with high affinity. Careful impairment of this interaction disrupted NaV1.5's ability to recover from inactivation. Such results support a paradigm of CaM‐facilitated recovery from inactivation (CFRI). How NaV–CaM, CaMKII and FGF/fibroblast growth factor homologous factor interactions affect the timing or function of CFRI in cardiomyocytes remain open questions that are discussed herein. Moreover whether CFRI dysfunction or premature activation underlie certain NaV channelopathies are important questions that will require further investigation. [ABSTRACT FROM AUTHOR]

Based on recent findings, an increased late sodium current (INa,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is INa,late and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased INa,late in heart diseases, and also discusses how the upregulated INa,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about INa,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials. [ABSTRACT FROM AUTHOR]

The voltage‐sensitive sodium channel (VSSC) is essential for the generation and propagation of action potentials. VSSC kinetics can be modified by producing different splice variants. The functionality of VSSC depends on features such as the voltage sensors, the selectivity filter and the inactivation loop. Mutations in Vssc conferring resistance to pyrethroid insecticides are known as knockdown resistance (kdr). We analysed the conservation of VSSC in both a broad scope and a narrow scope by three approaches: (1) we compared conservation of sequences and of differential exon use across orders of the Insecta; (2) we determined which kdr mutations were possible with a single nucleotide mutation in nine populations of Aedes aegypti; and (3) we examined the individual VSSC variation that exists within a population of Drosophila melanogaster. There is an increasing amount of transcript diversity possible from Diplura towards Diptera. The residues of the voltage sensors, selectivity filter and inactivation loop are highly conserved. The majority of exon sequences were >88.6% similar. Strain‐specific differences in codon constraints exist for kdr mutations in nine strains of A. aegypti. Three Vssc mutations were found in one population of D. melanogaster. This study shows that, overall, Vssc is highly conserved across Insecta and within a population of an insect, but that important differences do exist. [ABSTRACT FROM AUTHOR]

Erythromelalgia (EM) is a rare disorder characterized by erythematous, warm, painful extremities, which is often precipitated by cold conditions. The pathophysiology of EM is incompletely understood. Recent investigations have identified sodium channelopathy as a genetic cause for this pain condition, classified as primary inherited EM. Other subtypes are idiopathic EM and secondary EM. The management of pain in EM is challenging as no single therapy has been found to be effective. There is varying response to pharmacotherapy and significant variability within this clinical population, resulting in a stepwise trial and error approach. Consequently, EM is often associated with poorer health-related quality of life with higher morbidity. There is currently no consensus or guidelines on management of pain in EM. This is a review of the literature on management of pain using pharmacologic, procedural intervention and nonpharmacologic treatment in children and adults with EM. [ABSTRACT FROM AUTHOR]

Key points Voltage-gated sodium channels play a fundamental role in determining neuronal excitability., Specifically, voltage-gated sodium channel subtype NaV1.7 is required for sensing acute and inflammatory somatic pain in mice and humans but its significance in pain originating from the viscera is unknown., Using comparative behavioural models evoking somatic and visceral pain pathways, we identify the requirement for NaV1.7 in regulating somatic (noxious heat pain threshold) but not in visceral pain signalling., These results enable us to better understand the mechanisms underlying the transduction of noxious stimuli from the viscera, suggest that the investigation of pain pathways should be undertaken in a modality-specific manner and help to direct drug discovery efforts towards novel visceral analgesics., Abstract Voltage-gated sodium channel NaV1.7 is required for acute and inflammatory pain in mice and humans but its significance for visceral pain is unknown. Here we examine the role of NaV1.7 in visceral pain processing and the development of referred hyperalgesia using a conditional nociceptor-specific NaV1.7 knockout mouse (NaV1.7Nav1.8) and selective small-molecule NaV1.7 antagonist PF-5198007. NaV1.7Nav1.8 mice showed normal nociceptive behaviours in response to intracolonic application of either capsaicin or mustard oil, stimuli known to evoke sustained nociceptor activity and sensitization following tissue damage, respectively. Normal responses following induction of cystitis by cyclophosphamide were also observed in both NaV1.7Nav1.8 and littermate controls. Loss, or blockade, of NaV1.7 did not affect afferent responses to noxious mechanical and chemical stimuli in nerve-gut preparations in mouse, or following antagonism of NaV1.7 in resected human appendix stimulated by noxious distending pressures. However, expression analysis of voltage-gated sodium channel α subunits revealed NaV1.7 mRNA transcripts in nearly all retrogradely labelled colonic neurons, suggesting redundancy in function. By contrast, using comparative somatic behavioural models we identify that genetic deletion of NaV1.7 (in NaV1.8-expressing neurons) regulates noxious heat pain threshold and that this can be recapitulated by the selective NaV1.7 antagonist PF-5198007. Our data demonstrate that NaV1.7 (in NaV1.8-expressing neurons) contributes to defined pain pathways in a modality-dependent manner, modulating somatic noxious heat pain, but is not required for visceral pain processing, and advocate that pharmacological block of NaV1.7 alone in the viscera may be insufficient in targeting chronic visceral pain. [ABSTRACT FROM AUTHOR]

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The axon initial segment (AIS) is a highly specialized neuronal compartment that plays a key role in neuronal development and excitability. It concentrates multiple membrane proteins such as ion channels and cell adhesion molecules (CAMs) that are recruited to the AIS by the scaffold protein ankyrin G (ankG). The crucial function of ankG in the anchoring of AIS membrane components is well established, but a reciprocal role of membrane partners in ankG targeting and stabilization remained elusive. In rat cultured hippocampal neurons and cortical organotypic slices, we found that shRNA-mediated knockdown of ankG membrane partners (voltage-gated sodium channels (Nav) or neurofascin-186) led to a decrease of ankG concentration and perturbed the AIS formation and maintenance. These effects were rescued by expressing a recombinant AIS-targeted Nav or by a minimal construct containing the ankyrin-binding domain of Nav1.2 and a membrane anchor (mABD). Moreover, overexpressing mABD in mature neurons led to ankG mislocalization. Altogether, these results demonstrate that a tight and precocious association of ankG with its membrane partners is a key step for the establishment and maintenance of the AIS. [ABSTRACT FROM AUTHOR]

Antiepileptic drugs act on voltage gated sodium channels in many different ways: rufinamide is thought to influence the fast inactivation, so its anticonvulsant action could be similar to carbamazepine, whereas lacosamide enhances the slow inactivation; however some antidepressants were also described to act in the same way. Rufinamide, lacosamide, carbamazepine, fluoxetine and imipramine were tested using in vitro models of epileptiform activities. Extracellular local field potentials were recorded using hippocampal slices from immature rats and the pattern of epileptiform activities was analyzed. Seizure-like events (SLE), but not interictal bursts were sensitive to AEDs' action. Rufinamide increased interictal periods by prolonging preictal phase and reducing SLE duration, and was the only tested AED which reduced SLE frequency. Lacosamide's effect resembled that of fluoxetine in the low-Mg model: both drugs reduced markedly the SLE duration, but increased their frequency. Imipramine and fluoxetine irreversibly suppressed SLE in all slices. Some proconvulsive type of action on SLEs such as increasing preictal neuronal activity by rufinamide and increasing SLE frequency by lacosamide, fluoxetine and carbamazepine, were also observed. Newer drugs were more efficient than carbamazepine, and the anticonvulsant action of antidepressants on in vitro epileptiform activities may seem somewhat surprising. [ABSTRACT FROM AUTHOR]

Background: Anopheles culicifacies s.l. is one of the primary vectors of malaria in India responsible for the highest number of malaria cases. This vector is resistant to DDT in most parts of the country with indication of emerging resistance to pyrethroids. Since knockdown resistance (kdr) is known to confer cross-resistance between DDT and pyrethroids owing to a common target site of action, knowledge of prevalence of knockdown resistance (kdr) alleles is important from insecticide resistance management point of view. Methods: Nine populations of An. culicifacies belonging to five states of India, representing northern, western and central-east India, were screened for the presence of two alternative kdr mutations L1014F and L1014S using PCR-based assays. Dead and alive mosquitoes, following WHO standard insecticide susceptibility test against deltamethrin and DDT, were tested for allelic association. Results: L1014F mutation was recorded in all populations studied except from Haryana and Rajasthan states in northern India, with low frequencies ranging between 0.012 and 0.076; whereas presence of L1014S mutation was recorded in five populations only belonging to central-east India, with allelic frequencies ranging between 0.010 and 0.046. Both the kdr mutant alleles were found mostly in heterozygous condition without deviating from Hardy-Weinberg equilibrium. Both mutations showed protection against deltamethrin whereas only L1014S mutation showed protection against DDT when tested using additive model. Conclusions: The two L1014-kdr mutations, L1014F and L1014S, co-occurred in five populations belonging to Chhattisgarh and Odisha states of India whereas L1014F was present in all populations studied except populations from northern states. Both kdr mutations were found with very low allelic frequencies mostly in heterozygous condition and exhibited protection against deltamethrin. [ABSTRACT FROM AUTHOR]

Classical accommodation is a form of spike frequency adaptation in neurons whereby excitatory drive results in action potential output of gradually decreasing frequency. Here we describe an essential molecular component underlying classical accommodation in juvenile mouse hippocampal CA1 pyramidal neurons. A-type isoforms of fibroblast growth factor homologous factors (FHFs) bound to axoso-matic voltage-gated sodium channels bear an N-terminal blocking particle that drives some associated channels into a fast-onset, long-term inactivated state. Use-dependent accumulating channel blockade progressively elevates spike voltage threshold and lengthens interspike intervals. The FHF particle only blocks sodium channels from the open state, and mutagenesis studies demonstrate that this particle uses multiple aliphatic and cationic residues to both induce and maintain the long-term inactivated state. The broad expression of A-type FHFs in neurons throughout the vertebrate CNS suggests a widespread role of these sodium channel modulators in the control of neural firing. [ABSTRACT FROM AUTHOR]

In the work reported here, we have investigated the changes in the activation and fast inactivation properties of the rat brain voltage-gated sodium channel (rNav 1.2a) α subunit, expressed heterologously in the Chinese Hamster Ovary (CHO) cells, by short depolarizing prepulses (10 – 1000 ms). The time constant of recovery from fast inactivation (τfast) and steady-state parameters for activation and inactivation varied in a pseudo-oscillatory fashion with the duration and amplitude of a sustained prepulse. A consistent oscillation was observed in most of the steady-state and non-inactivating current parameters with a time period close to 225 ms, although a faster oscillation of time period 125 ms was observed in the τfast. The studies on the non-inactivating current and steady-state activation indicate that the phase of oscillation varies from cell to cell. Co-expression of the β1 subunit with the α subunit channel suppressed the oscillation in the charge movement per single channel and free energy of steady-state inactivation, although the oscillation in the half steady-state inactivation potential remained unaltered. Incidentally, the frequencies of oscillation in the sodium channel parameters (4–8 Hz) correspond to the theta component of network oscillation. This fast pseudo-oscillatory mechanism, together with the slow pseudo-oscillatory mechanism found in these channels earlier, may contribute to the oscillations in the firing properties observed in various neuronal subtypes and many pathological conditions. [ABSTRACT FROM AUTHOR]