Analysis of human Nav1.8 expressed in SH-SY5Y neuroblastoma cells

Dekker, Lodewijk V.; Daniels, Zoe; Hick, Caroline A.; Elsegood, Kathryn A.; Bowden, Sarah E. H.; Szestak, Tadge; Burley, J Russell; Southan, Andy; Cronk, David; James, Iain F.

doi:10.1016/j.ejphar.2005.10.035

Cited by 26 publications

(14 citation statements)

References 21 publications

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“…Benzazepinone derivatives are selective blockers of the Na v 1.5, Na v 1.7, and Na v 1.8 channels [251,253]. Clinical trials are ongoing with compounds which were characterized to block neuronal subtype sodium channels like Na v 1.8 (ralfinamide [259,260], lacosamide [261], ambroxol [262]). In addition to Na v 1.8, lacosamide inhibits Na v 1.3 and Na v 1.7.…”

Section: Synthetic Compoundsmentioning

confidence: 99%

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Andavan

Lemmens‐Gruber²

2011

CMC

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Voltage-gated sodium channels produce fast depolarization, which is responsible for the rising phase of the action potential in neurons, muscles and heart. These channels are very large membrane proteins and are encoded by ten genes in mammals. Sodium channels are a crucial component of excitable tissues; hence, they are a target for various neurotoxins that are produced by plants and animals for defence and protection, such as tetrodotoxin, scorpion toxins and batrachotoxin. Several mutations in various sodium channel subtypes cause multiple inherited diseases known as channelopathies. When these mutated sodium channel subtypes are expressed in various tissues, channelopathies in brain, skeletal muscle and cardiac muscle develop as well as neuropathic pain. In this review, we discuss aspects of voltage-gated sodium channel genes with an emphasis on cardiac muscle sodium channels. In addition, we report novel mutations that underlie a spectrum of diseases, such as Brugada, long QT syndrome and inherited conduction disorders. Furthermore, this review explains commonalities and differences among the channel subtypes, the channelopathies caused by the sodium channel gene mutation and the specificity of toxins and blockers of the channel subtypes.

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Section: Synthetic Compoundsmentioning

confidence: 99%

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Andavan

Lemmens‐Gruber²

2011

CMC

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“…Nav1.8 channels interact with various commercially available compounds such as menthol [42], lidocaine [43], tetracaine [44], vinpocetine [45], ambroxol [46], lamotrigine [44], mexilitine [47], veratridine [48], and A-803467 [49], whereas very few animal toxins have been shown to be capable of reshaping Nav1.8 currents. ProTx-I and ProTx-II from the Thrixopelma pruriens tarantula were among the first spider toxins to be characterized as potent inhibitors of Nav1.8 opening [50], possibly by stabilizing one or more of its voltage sensors in the closed state [25,51,52] (Figure 1a,c,d).…”

Section: Pharmacological Properties Of Nav18 and Nav19mentioning

confidence: 99%

Animal Toxins Can Alter the Function of Nav1.8 and Nav1.9

Bosmans

2012

Toxins

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Human voltage-activated sodium (Nav) channels are adept at rapidly transmitting electrical signals across long distances in various excitable tissues. As such, they are amongst the most widely targeted ion channels by drugs and animal toxins. Of the nine isoforms, Nav1.8 and Nav1.9 are preferentially expressed in DRG neurons where they are thought to play an important role in pain signaling. Although the functional properties of Nav1.8 have been relatively well characterized, difficulties with expressing Nav1.9 in established heterologous systems limit our understanding of the gating properties and toxin pharmacology of this particular isoform. This review summarizes our current knowledge of the role of Nav1.8 and Nav1.9 in pain perception and elaborates on the approaches used to identify molecules capable of influencing their function.

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“…In recombinant systems ralfinamide confirmed its activity for specific channels subtypes such as Nav1.8 [5] , Nav1.7 [6] , Nav1.3, and Cav2.2, [unpubl. data], all recognized key players in the pathophysiology of pain.…”

Section: Introductionmentioning

confidence: 99%

Disposition and Metabolism of Ralfinamide, a Novel Na-Channel Blocker, in Healthy Male Volunteers

Bauer¹,

Bliesath²,

Leuratti³

et al. 2010

Pharmacology

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Ralfinamide is an α-aminoamide derivative with ion channel blocking properties, acting both peripherally and centrally through different molecular targets important in pain control. Absorption, blood and plasma time courses, and urinary and faecal excretion of total radioactivity were assessed in 6 male healthy volunteers administered a single oral dose of 320 mg ¹⁴C-(S)-ralfinamide. Pharmacokinetics of the parent drug were investigated over 120 h, urinary and plasma metabolites up to 192 h post-dose. ¹⁴C-(S)-ralfinamide was rapidly and completely absorbed. Ralfinamide and the dealkylated ralfinamide metabolite (NW-1716) represented the majority of plasma radioactivity. Plasma elimination of the parent compound occurred mono-exponentially (half-life approx. 15 h). ¹⁴C-radioactivity was eliminated in a bi-phasic manner (terminal half-life of 60 and 24 h for plasma and whole blood, respectively). Plasma-concentrations of unchanged ralfinamide were significantly lower than radioactivity concentrations, indicating metabolism of the parent compound. At 192 h post-dose the total balance of radioactivity was almost complete (95%). The main route of excretion was via the kidneys (94% of the dose). Major metabolites identified in urine and plasma were the N-dealkylated acid of ralfinamide and deaminated ralfinamide acid (NW-1799). Other metabolites, in particular the product of glucuronide conjugation N-dealkylated-β-glucuronide, were identified.

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Analysis of human Nav1.8 expressed in SH-SY5Y neuroblastoma cells

Cited by 26 publications

References 21 publications

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Voltage-Gated Sodium Channels: Mutations, Channelopathies and Targets

Animal Toxins Can Alter the Function of Nav1.8 and Nav1.9

Disposition and Metabolism of Ralfinamide, a Novel Na-Channel Blocker, in Healthy Male Volunteers

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