Inhibition of High Voltage-Activated Calcium Channels by Spider Toxin PnTx3-6

Vieira, Luciene Bruno; Kushmerick, Christopher; Hildebrand, Michael E.; Garcı́a, Esperanza; Stea, Antony; Cordeiro, Marta N.; Richardson, Michael; Gomez, Marcus V.; Snutch, Terrance P.

doi:10.1124/jpet.105.087023

Cited by 102 publications

(76 citation statements)

References 38 publications

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“…Our results suggest that the contaminating 4920-Da peptide in the initial Tx1 sample R21 could be toxin Tx3-3 based on its partial Nterminal sequence. The Tx3 fraction includes several toxins that are antagonists of high-voltage-activated calcium channels with a preference for Ca v 2 channels (Cassola et al, 1998;Leã o et al, 2000;Gouvêa dos Santos et al, 2002;Vieira et al, 2005). Thus, the contaminating peptide may account for Tx1 initially being designated inappropriately as a calcium channel blocker.…”

Section: Discussionmentioning

confidence: 99%

Phoneutria nigriventerToxin 1: A Novel, State-Dependent Inhibitor of Neuronal Sodium Channels That Interacts with μ Conotoxin Binding Sites

Martin-Moutôt

Mansuelle²,

Alcaraz³

et al. 2006

Mol Pharmacol

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A toxin was purified to homogeneity from the venom of the South American armed spider Phoneutria nigriventer and found to have a molecular mass of 8600 Da and a C-terminally amidated glycine residue. It appears to be identical to Toxin 1 (Tx1) isolated previously from this venom. Tx1 reversibly inhibited sodium currents in Chinese hamster ovary cells expressing recombinant sodium (Na v 1.2) channels without affecting their fast biophysical properties. The kinetics of inhibition of peak sodium current varied with membrane potential, with on-rates increasing and off-rates decreasing with more depolarized holding potentials in the Ϫ100 to Ϫ50 mV range. Thus, the apparent affinity of Tx1 for the channel increases as the membrane is depolarized. A mono[125 I]iodo-Tx1 derivative displayed high-affinity binding to a single class of sites (K D ϭ 80 pM, B max ϭ 0.43 pmol/mg protein) in rat brain membranes. Solubilized binding sites were immunoprecipitated by antibodies directed against a conserved motif in sodium channel ␣ subunits. 125 I-Tx1 binding was competitively displaced by conotoxin GIIIB (IC 50 ϭ 0.5 M) but not by 1 M tetrodotoxin. However, the inhibition of 125 I-Tx1 binding by conotoxin GIIIB was abrogated in the presence of tetrodotoxin (1 M). Patch-clamp and binding data indicate that P. nigriventer Tx1 is a novel, state-dependent sodium-channel blocker that binds to a site in proximity to pharmacological site 1, overlapping conotoxin but not tetrodotoxin binding sites.

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Section: Discussionmentioning

confidence: 99%

Phoneutria nigriventerToxin 1: A Novel, State-Dependent Inhibitor of Neuronal Sodium Channels That Interacts with μ Conotoxin Binding Sites

Martin-Moutôt

Mansuelle²,

Alcaraz³

et al. 2006

Mol Pharmacol

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“…The spinal administration of x-conotoxin MVIIA, a cone snail Conus magus toxin that blocks Cav2.2, reduced the hyperalgesia from nerve injury or inflammation in preclinical behavioral models of chronic pain (Malmberg and Yaksh 1995;Bowersox et al 1996;Scott et al 2002). Moreover, the intrathecal administration of the spider Pha1b, a reversible inhibitor of N-type VSCCs (Vieira et al 2005), induced an analgesic effect in rodent models of acute and chronic pain with few adverse effects (Souza et al 2008). Therefore, the current study was designed to evaluate the antinociceptive effect of Pha1b and x-conotoxin MVIIA in a model of inflammatory and neuropathic pain induced by Complete Freund's adjuvant (CFA) and chronic constrictive injury (CCI), respectively, in rats.…”

Section: Introductionmentioning

confidence: 98%

An Evaluation of the Antinociceptive Effects of Phα1β, a Neurotoxin from the Spider Phoneutria nigriventer, and ω-Conotoxin MVIIA, a Cone Snail Conus magus Toxin, in Rat Model of Inflammatory and Neuropathic Pain

et al. 2012

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Voltage-sensitive calcium channels (VSCCs) underlie cell excitability and are involved in the mechanisms that generate and maintain neuropathic and inflammatory pain. We evaluated in rats the effects of two VSCC blockers, ω-conotoxin MVIIA and Phα1β, in models of inflammatory and neuropathic pain induced with complete Freund's adjuvant (CFA) and chronic constrictive injury (CCI), respectively. We also evaluated the effects of the toxins on capsaicin-induced Ca(2+) influx in dorsal root ganglion (DRG) neurons obtained from rats exposed to both models of pain. A single intrathecal injection of Phα1β reversibly inhibits CFA and CCI-induced mechanical hyperalgesia longer than a single injection of ω-conotoxin MVIIA. Phα1β and MVIIA also inhibited capsaicin-induced Ca(2+) influx in DRG neurons. The inhibitory effect of Phα1β on capsaicin-induced calcium transients in DRG neurons was greater in the CFA model of pain, while the inhibitory effect of ω-conotoxin MVIIA was greater in the CCI model. The management of chronic inflammatory and neuropathic pain is still a major challenge for clinicians. Phα1β, a reversible inhibitor of VSCCs with a preference for N-type Ca(2+) channels, has potential as a novel therapeutic agent for inflammatory and neuropathic pain. Clinical studies are necessary to establish the role of Phα1β in the treatment of chronic pain.

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“…The partial proteome of this venom was recently described (Richardson et al, 2006). Most of the toxins that have been purified from this venom seem to act on ionic channels, including those for sodium (Araujo et al, 1993;De Lima et al, 2007;Martin-Moutot et al, 2006;Matavel et al, 2002), calcium (Dos Santos et al, 2002;Guatimosim et al, 1997;Leão et al, 2000;Vieira et al, 2005) and potassium (Kushmerick et al, 1999). Some of these toxins have insecticidal activity (for a review see De Lima et al, 2007), interfer with the uptake of L-glutamate on synaptosomes of rat brain (Mafra et al, 1999) and inhibit NMDA-evoked currents in rat hippocampal neurons (Figueiredo et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile function

Nunes

Costa‐Goncalves

Lanza

et al. 2008

Toxicon

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The venom of the spider Phoneutria nigriventer contains several toxins that have bioactivity in mammals and insects. Accidents involving humans are characterized by various symptoms including penile erection. Here we investigated the action of Tx2-6, a toxin purified from the P. nigriventer spider venom that causes priapism in rats and mice. Erectile function was evaluated through changes in intracavernosal pressure/mean arterial pressure ratio (ICP/MAP) during electrical stimulation of the major pelvic ganglion (MPG) of normotensive and deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Nitric oxide (NO) release was detected in cavernosum slices with fluorescent dye (DAF-FM) and confocal microscopy. The effect of Tx2-6 was also characterized after intracavernosal injection of a non-selective nitric oxide synthase (NOS) inhibitor, L-NAME. Subcutaneous or intravenous injection of Tx2-6 potentiated the elevation of ICP/MAP induced by ganglionic stimulation. L-NAME inhibited penile erection and treatment with Tx2-6 was unable to reverse this inhibition. Tx2-6 treatment induced a significant increase of NO release in cavernosum tissue. Attenuated erectile function of DOCA-salt hypertensive rats was fully restored after toxin injection. Tx2-6 enhanced erectile function in normotensive and DOCA-salt hypertensive rats, via the NO pathway. Our studies suggest that Tx2-6 could be important for development of new pharmacological agents for treatment of erectile dysfunction.

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Inhibition of High Voltage-Activated Calcium Channels by Spider Toxin PnTx3-6

Cited by 102 publications

References 38 publications

Phoneutria nigriventerToxin 1: A Novel, State-Dependent Inhibitor of Neuronal Sodium Channels That Interacts with μ Conotoxin Binding Sites

Phoneutria nigriventerToxin 1: A Novel, State-Dependent Inhibitor of Neuronal Sodium Channels That Interacts with μ Conotoxin Binding Sites

An Evaluation of the Antinociceptive Effects of Phα1β, a Neurotoxin from the Spider Phoneutria nigriventer, and ω-Conotoxin MVIIA, a Cone Snail Conus magus Toxin, in Rat Model of Inflammatory and Neuropathic Pain

Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile function

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