Phoneutria nigriventer ω-Phonetoxin IIA Blocks the Cav2 Family of Calcium Channels and Interacts with ω-Conotoxin-binding Sites

Santos, Raquel Gouvêa dos; Renterghem, Catherine Van; Martin-Moutôt, Nicole; Mansuelle, Pascal; Cordeiro, Marta N.; Diniz, Carlos R.; Mori, Yasuo; Lima, Maria Elena de; Seagar, Michael

doi:10.1074/jbc.m112348200

Cited by 60 publications

(47 citation statements)

References 23 publications

(18 reference statements)

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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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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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“…In the present study, we examined PnTx3-6, a member of the PhTx3 fraction (Cordeiro et al, 1993) that includes two other peptides that bind and inhibit HVA Ca 2ϩ channels -PnTx3-3 (Leã o et al, 2000) and -PnTx3-4, a peptide essentially identical to the HVA channel blocker -phonetoxin IIa (Cassola et al, 1998;Dos Santos et al, 2002).…”

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confidence: 99%

“…In Table 1, we present the sequence of PnTx3-6 aligned with other peptide toxins exhibiting some sequence similarity and with known activity on vertebrate HVA Ca 2ϩ channels. One of these, -phonetoxin IIa, was also isolated from P. nigriventer venom and potently inhibits rat L-and N-type currents in ␤ cells and dorsal root ganglion neurons, respectively (Cassola et al, 1998), as well as heterologously expressed P/Q-, N-, and R-type currents (Dos Santos et al, 2002). The -Aga toxins IIIA and IIIB, which inhibit vertebrate HVA Ca 2ϩ channels (Mintz, 1994;Yan and Adams, 2000;McDonough et al, 2002), exhibit 27% (15 amino acids) and 25% (14 amino acids) identity with PnTx3-6, respectively.…”

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confidence: 99%

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

Vieira¹,

Kushmerick²,

Hildebrand³

et al. 2005

J Pharmacol Exp Ther

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102

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Animal peptide toxins have become powerful tools to study structure-function relationships and physiological roles of voltage-activated Ca 2ϩ channels. In the present study, we investigated the effects of PnTx3-6, a neurotoxin purified from the venom of the spider Phoneutria nigriventer on cloned mammalian Ca 2ϩ channels expressed in human embryonic kidney 293 cells and endogenous Ca 2ϩ channels in N18 neuroblastoma cells. Whole-cell patch-clamp measurements indicate that PnTx3-6 reversibly inhibited L-(␣ 1C

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“…There are several peptidic N-type calcium channel blockers, such as ω-conotoxin GVIA, [12][13][14] MVIIA, 15 CVID (also known as AM336), CVIA, CVIB, CVIC, SVIB, TVIA, 16 CNVIIA, 17 PtxIIA, 18 ω-AgaIIIA, 19 MVIIC, [20][21][22] and huwentoxin. 23 GVIA, isolated from the venom of Conus geographus, is a 27-aminoacid peptide that is a potent and selective blocker of N-type calcium channels.…”

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confidence: 99%

High-Throughput Screening for N-Type Calcium Channel Blockers Using a Scintillation Proximity Assay

Zhang¹,

Kauffman²,

Yagel³

et al. 2006

SLAS Discovery

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N-type calcium channels located on presynaptic nerve terminals regulate neurotransmitter release, including that from the spinal terminations of primary afferent nociceptors. Accordingly, N-type calcium channel blockers may have clinical utility as analgesic drugs. A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. To develop a small-molecule N-type calcium channel blocker, the authors developed a 96-well plate high-throughput screening scintillation proximity assay (SPA) for N-type calcium channel blockers using [125 I]-labeled ω-conotoxin GVIA as a channel-specific ligand. Assay reagents were handled using Caliper's Allegro automation system, and bound ligands were detected using a PerkinElmer TopCount. Using this assay, more than 150,000 compounds were screened at 10 µM and approximately 340 compounds were identified as hits, exhibiting at least 40% inhibition of [125 I]GVIA binding. This is the 1st demonstration of the use of [ 125 I]-labeled peptides with SPA beads to provide a binding assay for the evaluation of ligand binding to calcium channels. This assay could be a useful tool for drug discovery. (Journal of Biomolecular Screening 2006:672-677)

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Phoneutria nigriventer ω-Phonetoxin IIA Blocks the Cav2 Family of Calcium Channels and Interacts with ω-Conotoxin-binding Sites

Cited by 60 publications

References 23 publications

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

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

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

High-Throughput Screening for N-Type Calcium Channel Blockers Using a Scintillation Proximity Assay

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