Binding sites and actions of Tx1, a neurotoxin from the venom of the spider Phoneutria nigriventer, in guinea pig ileum

Santos, Raquel Gouvêa dos; Diniz, Carlos R.; Cordeiro, Marta N.; Lima, M.E. de

doi:10.1590/s0100-879x1999001200019

Cited by 16 publications

(8 citation statements)

References 16 publications

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“…Nonetheless, PnTx1 awaits further investigation in order to elucidate its Cav channel interaction. Using similar competitive binding experiments it was shown that 125 I-PnTx1 partially blocked the PhTx2 induced activity in myenteric plexus-longitudinal muscle preparations (Santos et al, 1999). Since PhTX2 is the fraction that contains mainly sodium channel toxins, this observation hinted towards an activity of PnTx1 on Nav channels.…”

Section: Phtx1mentioning

confidence: 84%

“…fraction PhTx3, which contains several calcium channel modulating peptides. However, labeled PnTx1 did not compete with ω-conotoxin GVIA, a calcium channel inhibiting toxin isolated from cone snail venom (Santos et al, 1999). This rather contrary result was later attributed to the presence of a small contamination with PnTx3-3.…”

Section: Phtx1mentioning

confidence: 92%

“…Experiments using a highly purified PnTx1 showed that this toxin partially displaced the calcium-antagonist dihydropyridine derivative 3H-PN200-110 in GH3 cell membranes. Furthermore, a 50% inhibition of the calcium influx in GH3 cells was observed after application of 1 μM PnTx1 (Santos et al, 1999). On the other hand, experiments with the recombinant PnTx1 (rPnTx1) showed no modification in the calcium currents of dorsal root ganglia (DRG) neurons (Silva et al, 2012).…”

Section: Phtx1mentioning

confidence: 99%

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Phoneutria nigriventer venom: A pharmacological treasure

Peigneur

Lima

Tytgat

2018

Toxicon

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Section: Phtx1mentioning

confidence: 84%

Section: Phtx1mentioning

confidence: 92%

Section: Phtx1mentioning

confidence: 99%

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Phoneutria nigriventer venom: A pharmacological treasure

Peigneur

Lima

Tytgat

2018

Toxicon

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“…The cyanosis seen in some patients probably reflects a combination of respiratory disturbances, such as pulmonary edema resulting in poor oxygenation, cardiac failure/shock, and, more rarely, marked peripheral direct vasoconstriction. Vomiting and abdominal pain may indicate a stimulatory effect on the gastrointestinal tract, possibly through a combination involving the activation of autonomic pathways, the release of neuropeptides, direct activation of smooth muscle by toxins such as PhTx1 (Tx1) (Santos et al 1999), and the low molecular mass fraction of the venom that contains tachykinin-like venom peptides (Pimenta et al 2005). In rats, PNV delays gastric emptying partly through a catecholaminemediated mechanism (Bucaretchi and Collares 1996).…”

Section: Other Manifestationsmentioning

confidence: 99%

Envenomation by Wandering Spiders (Genus Phoneutria)

Bucaretchi¹,

Bertani²,

Capitani³

et al. 2017

Toxinology

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Spiders of the genus Phoneutria, commonly known as wandering or banana spiders, are found in southern Central America (Costa Rica) and throughout South America east of the Andes into northern Argentina. Eight species, classified as Amazonian (P. fera, P. reidyi, and P. boliviensis) and non-Amazonian (P. keyserlingi, P. pertyi, P. eickstedtae, P. bahiensis, and P. nigriventer), have been described. Most of the clinically important bites by this genus occur in Brazil (~4,000 cases per year), with only 0.5% being severe. Local pain is the major symptom reported after most bites and involves peripheral (tachykinin (neurokinin NK 1 and NK 2) and glutamate receptors) and central (spinal) mechanisms (neurokinins, excitatory amino acids, nitric oxide, proinflammatory cytokines, and prostanoids). Other local features observed in envenomed patients include edema, erythema, radiating pain, sweating, fasciculation, and paresthesia. Systemic manifestations are less common and may include diaphoresis, tachycardia, arterial hypertension, agitation, prostration, sialorrhea, vomiting, tachypnea, pallor, hypothermia, cyanosis, diarrhea, and priapism. Shock and pulmonary edema, the main severe complications, are uncommon and possibly related to increased sympathetic activity and a systemic inflammatory response, although no sequential serum catecholamine, nitric oxide, and interleukin levels have been measured in prospective case series of human envenomations by Phoneutria spp. Most cases are treated symptomatically, with antivenom being recommended only for patients who develop important systemic clinical manifestations; such manifestations occur in~3% of cases and involve mainly children <10 years old and adults >70 years old. Fifteen deaths attributed to Phoneutria spp. have been reported in Brazil since 1903, but in only two of these cases are there sufficient details to confirm a causal nexus.

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“…They are similar in size to scorpion a and b toxins that also target Na V channels (Rodriguez de la Vega and Possani, 2005), but they have no sequence homology and contain a larger number of disulfide bonds. Preliminary studies suggested that m-CNTX-Pn1a might target vertebrate Ca V channels (dos Santos et al, 1999Santos et al, , 2002) but more recent studies have shown that it is a state-dependent blocker of rat Na V 1.2 that binds in the vicinity of channel site 1 (Martin-Moutot et al, 2006). The high level of sequence identity suggests that all members of this family will have the same pharmacology.…”

Section: Nasptx Familymentioning

confidence: 99%

Developing novel analgesics to treat chronic pain: inhibiting voltage gated sodium channel 1.7 with spider-venom peptides

Arachchilage¹

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Chronic pain is responsible for great physical, mental and economic loss. While there are diverse methods available for managing pain, such as NSAID, opioids and local anesthetics, common issues associated such as addiction and tolerance highlights the unmet demand for a novel analgesic aimed at a novel target.Numerous reports on individuals suffering from loss of function mutations in SCN9A marker, which leads to complete inability to feel pain, yet otherwise normal physiology, has led to the recognition of voltage gated sodium channel 1.7 (Na V 1.7) as a prime pain target.Other reports of gain of function mutations that lead to conditions such as paroxysmal extreme pain disorder and primary erythromelalgia confirms the validity of this target.However the presence of nine closely related subtypes of voltage gated sodium channels, Na V 1.1-Na V 1.9 introduces complications as any cross inhibition may lead to detrimental results. For example inhibition of Na V 1.5 subtype could result in cardiac arrhythmia to complete cardiac arrest and death. Therefor it is of utmost importance that any pharmaceutical agent used to inhibit Na V 1.7 is highly specific for Na V 1.7 and display no cross reactivity on other voltage gated channels.Spiders are one of the most successful terrestrial predators; their venoms have evolved over many millions of years to selectively and potently inhibit nervous system targets in order to rapidly paralyze their prey. Spider-venom peptidomes have been identified as one of the largest known libraries of compounds with very high potency and specificity towards nervous system targets.Spider toxins listed in the Arachnoserver database have been classified into 12 families of sodium channel toxins (NaSpTx), denoted NaSpTx Families 1-12, based on the level of sequence conservation and intercystine spacing. NaSpTx family 2 is the largest toxin family; it comprises 34 peptides of theraphosid origin.This thesis primarily aims at discovering novel inhibitors of Na V 1.7. However the intriguing fact that people suffering form congenital indifference to pain also suffers form anosmia, has lead to efforts of understanding the role of Na V 1.7 in olfaction. This study has been iii completed with the finding that Na V 1.7 is located along axons of olfactory neurones. These findings have been published and research article is attached as chapter 4.During the initial discovery phase of this project, an assay guided fractionation method was used to identify Na V 1.7 inhibitors form six spider venoms. This resulted in nine fully sequenced peptides where four of these belonged to NaSpTx family 2. This included the well-known β/ω-TRTX-Tp1a (Protoxin1). Three novel peptides discovered were named β-TRTX-Pe1a, µ-TRTX-Pe1b, and U-TRTX-Pa1a.A complete alanine scan of β/ω-TRTX-Tp1a on Na V 1.7 was conducted using a Xenopus laevis oocyte based tethered toxin method. Residues that were important for Na V 1.7 binding were mapped onto the three-dimensional structure of β/ω-TRTX-Tp1a. Three novel toxin peptides β-TR...

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Binding sites and actions of Tx1, a neurotoxin from the venom of the spider Phoneutria nigriventer, in guinea pig ileum

Cited by 16 publications

References 16 publications

Phoneutria nigriventer venom: A pharmacological treasure

Phoneutria nigriventer venom: A pharmacological treasure

Envenomation by Wandering Spiders (Genus Phoneutria)

Developing novel analgesics to treat chronic pain: inhibiting voltage gated sodium channel 1.7 with spider-venom peptides

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