Nav 1.7 blocker

Human-induced pluripotent stem cells (iPS cells) are efficiently differentiated into sensory neurons. These cells express the voltage-gated sodium channel NaV 1.7, which is a validated pain target. NaV 1.7 deficiency leads to pain insensitivity, whereas NaV 1.7 gain-of-function mutants are associated with chronic pain. During differentiation, the sensory neurons start spontaneous action potential firing around day 22, with increasing firing rate until day 40. Here, we used CRISPR/Cas9 genome editing to generate a HA-tag NaV 1...

Epidural block using lidocaine, a non-selective blocker of voltage-gated sodium channels (Nav), has demonstrated efficacy in the treatment of severe plaque psoriasis in a limited number of cases. This study aimed to evaluate the effectiveness and safety of epidural lidocaine block in adult patients with severe, treatment-resistant plaque psoriasis. This was an open-label pilot study. Patients with severe plaque-type psoriasis unresponsive to at least one systemic treatment were enrolled for a 1-week epidural lidocaine block and followed up for 48 weeks...

Comparative studies using reptiles as experimental animals in pain research could expand our knowledge on the evolution and adaptation of pain mechanisms. Currently, there are no data reported on the involvement of voltage-gated sodium ion channels on nociception in reptiles. The aim of this study was to investigate the involvement of Nav1.3, Nav1.7, and Nav1.8 ion channels in nociception in Speke's hinge-back tortoise. ICA 121341 (selective blocker for Nav1.1/Nav1.3), NAV 26 (selective blocker for Nav1.7), and A803467 (selective blocker for Nav1...

Neuronal electrochemical signals involve the flux of sodium ions through voltage-gated sodium channels (NaV ) located in the neurolemma. Of the nine sodium channel subtypes, NaV -1.7, 1.8, and 1.9 are predominantly located on nociceptors, making them prime targets to control pain. This review highlights some of the latest discoveries targeting NaV channel activity, including: (1) charged local anaesthetic derivatives; (2) NaV channel toxins and associated small peptide blockers; (3) regulation of NaV channel accessory proteins; and (4) genetic manipulation of NaV channel function...

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1 . Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2 , their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav 1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav 1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell...

SCN2A encodes NaV 1.2, an excitatory neuron voltage-gated sodium channel and a major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with the nature of SCN2A variant dysfunction and can be divided into gain-of-function (GoF) cases with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age.We established and assessed patient induced pluripotent stem cell (iPSC) - derived neuronal models for two recurrent SCN2A DEE variants with GoF R1882Q and LoF R853Q associated with early- and late-onset DEE, respectively...

Voltage-gated sodium channels (Nav ) are protein complexes that play fundamental roles in the transmission of signals in the nervous system, at the neuromuscular junction and in the heart. They are mainly present in excitable cells where they are responsible for triggering action potentials. Dysfunctions in Nav ion conduction give rise to a wide range of conditions, including neurological disorders, hypertension, arrhythmia, pain and cancer. Nav family 1 is composed of nine members, named numerically from 1 to 9...

Voltage-gated sodium (NaV ) channels are transmembrane proteins that play a critical role in electrical signaling in the nervous system and other excitable tissues. µ-Conotoxins are peptide toxins from the venoms of marine cone snails (genus Conus) that block NaV channels with nanomolar potency. Most species of the subgenera Textilia and Afonsoconus are difficult to acquire; therefore, their venoms have yet to be comprehensively interrogated for µ-conotoxins. The goal of this study was to find new µ-conotoxins from species of the subgenera Textilia and Afonsoconus and investigate their selectivity at human NaV channels...

Disulfide-rich peptide toxins have long been studied for their ability to inhibit voltage-gated sodium channel subtype NaV 1.7, a validated target for the treatment of pain. In this study, we sought to combine the pore blocking activity of conotoxins with the gating modifier activity of spider toxins to design new bivalent inhibitors of NaV 1.7 with improved potency and selectivity. To do this, we created an array of heterodimeric toxins designed to target human NaV 1.7 by ligating a conotoxin to a spider toxin and assessed the potency and selectivity of the resulting bivalent toxins...

To evaluate the effects of antipruritic drugs, it is important to determine whether the neural responses induced by physiological itch stimuli are suppressed. Although there are several behavioral assessments for topical antipruritic drugs applied to the skin, there are few established methods at neuronal levels using in vivo electrophysiological recordings for predicting local efficacy of antipruritic drugs for cutaneous application. To establish an assessment of topical antipruritic drugs applied to skin using in vivo extracellular recording from neurons in the superficial dorsal horn, we examined the relationships between itch-related biting behavior and spinal neuronal responses elicited by intradermal injection of pruritogen serotonin (5-HT) in hairless mice...

μ-Conotoxin KIIIA, a selective blocker of sodium channels, has strong inhibitory activity against several Nav isoforms, including Nav 1.7, and has potent analgesic effects, but it contains three pairs of disulfide bonds, making structural modification difficult and synthesis complex. To circumvent these difficulties, we designed and synthesized three KIIIA analogs with one disulfide bond deleted. The most active analog, KIIIA-1, was further analyzed and its binding pattern to hNav 1.7 was determined by molecular dynamic (MD) simulations...

Tramadol is an opioid analog used to treat chronic and acute pain. Intradermal injections of tramadol at hundreds of millimoles have been shown to produce a local anesthetic effect. We used the whole-cell patch-clamp technique in this study to investigate whether tramadol blocks the sodium current in HEK293 cells, which stably express the pain threshold sodium channel Nav 1.7 or the cardiac sodium channel Nav 1.5. The half-maximal inhibitory concentration of tramadol was 0.73 mM for Nav 1.7 and 0.43 mM for Nav 1...

Venom-derived NaV 1.7 channel blockers have promising prospects in pain management. The 34-residue tarantula peptide GpTx-1 is a potent NaV 1.7 channel blocker. Its powerful analog [Ala5 , Phe6 , Leu26 , Arg28 ]GpTx-1 (GpTx-1-71) displayed excellent NaV 1.7 selectivity and analgesic properties in mice. The current study aimed to elucidate the anti-hyperalgesic activities of GpTx-1-71 in inflammatory pain and reveal the underlying mechanisms. Our results demonstrated that intrathecal and intraplantar injections of GpTx-1-71 dose-dependently attenuated CFA-induced inflammatory hypersensitivity in rats...

Voltage-gated sodium channels (Nav s) play a crucial electrical signaling role in neurons. Nav -isoforms present in peripheral sensory neurons and dorsal root ganglia of the spinal cord are critically involved in pain perception and transmission. While these isoforms, particularly Nav 1.7, are implicated in neuropathic pain disorders, changes in the functional state and expression levels of these channels have not been extensively studied in vivo. Radiocaine, a fluorine-18 radiotracer based on the local anesthetic lidocaine, a non-selective Nav blocker, has previously been used for cardiac Nav 1...

Voltage-gated sodium channel NaV 1.7 plays essential roles in pain and odor perception. NaV 1.7 variants cause pain disorders. Accordingly, NaV 1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human NaV 1.7/β1/β2 complexed with inhibitors XEN907, TC-N1752 and NaV 1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall...

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Nav 1.5 (and its current, INa ) and Kv 1.5 (and its current, IKur ) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles...

Isolated smooth muscle cells (SMC) from mouse bronchus were studied using the whole-cell patch clamp technique at ~21o C. Stepping from -100 mV to -20 mV evoked inward currents of mean amplitude -275 pA. These inactivated (tau=1.1 ms) and were abolished when external Na+ was substituted with N-Methyl-D-glucamine. In current-voltage protocols, current peaked at -10 mV and reversed between +20 and +30 mV. The V1/2 sof activation and inactivation were -25 & -86 mV, respectively. The current was highly sensitive to tetrodotoxin (IC50 =1...

The dorsal root ganglia-localized voltage-gated sodium (Nav ) channel Nav 1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Nav 1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Nav 1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 Å. The first voltage-sensing domain (VSDI ) displays three different conformations...

The voltage-gated sodium channel Nav 1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav 1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav 1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav 1.7 blockers. The design of these molecules focused on maintaining potency at Nav 1...

The human TE671 cell line was originally used as a model of medulloblastoma but has since been reassigned as rhabdomyosarcoma. Despite the characterised endogenous expression of voltage-sensitive sodium currents in these cells, the specific voltage-gated sodium channel (VGSC) subtype underlying these currents remains unknown. To profile the VGSC subtype in undifferentiated TE671 cells, endpoint and quantitative reverse transcription-PCR (qRT-PCR), western blot and whole-cell patch clamp electrophysiology were performed...