Spider Toxin Card | ArachnoServer

Toxin Name	β/ω-theraphotoxin-Tp2a
Source Species	*Thrixopelma pruriens* (Green velvet tarantula)
Toxin Group	Theraphotoxin
Description	β/ω-TRTX-Tp2a blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium (Nav) channels by shifting the voltage dependence of channel activation to more positive potentials. The toxin is at least 100-fold more potent against Nav1.7 than other human Nav channel subtypes. Has no significant effect on Kv1.2, Kv1.3, Kv1.5, and Kv2.1 channels. Also inhibits activation of human Cav3.1 channels at much higher doses. The pharmacophore shown in the figure below, which is comprised exclusively of hydrophobic and cationic residues, is for interaction with Nav1.5 channels. The binding site(s) for β/ω-TRTX-Tp2a on Nav channels remains to be unequivocally determined, but Nav1.5 chimeras indicate that it does not bind to the pharmacologically defined Nav channel sites 3 or 4. Neutralization of gating charges in the voltage sensor (S4) of domain II of Nav1.2 prevents the effect of the toxin on gating current. Thus, it has been suggested that the toxin acts by trapping the voltage sensor of Nav channel domain II in the resting state, impeding outward gating movement of the IIS4 transmembrane segment of the channel. β/ω-TRTX-Tp2a is lethal to rats when injected intravenously at 1.0 mg/kg (although doses of 0.01 and 0.1 mg/kg are well tolerated) or by intrathecal administration at 0.1 mg/kg. The toxin was not efficacious in rodent models of acute and inflammatory pain when administered intravenously at 0.01 or 0.1 mg/kg or intrathecally at 0.001 or 0.01 mg/kg. The latter intrathecal dose transiently reduced muscle tone and impaired motor function even though systemic levels at 4 hours after toxin administration were below the level of detection (3 nM). Toxins with very similar primary structure have been reported from two different theraphosid spiders, Grammostola rosea (κ-TRTX-Gr2a, a weak blocker of mechanosensitive channels in rat astrocytes (Kd ~ 6 μM)) and Paraphysa scrofa (κ-TRTX-Ps1a, a blocker of vertebrate voltage-gated potassium channels Kv4.2 and Kv4.3)
Discovered	2002

Sex: female, Prosoma length: 27mm
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This toxin last updated on Feb 08, 2012

Taxonomy

Biological Activity

Neurotoxin

Molecular Target	IC50	Kd	Comment
Sodium channel, voltage-gated (vertebrate): Na_V1.5	79.0 nM		Inhibition by native toxin of human Nav1.5 expressed in HEK-293 cells
Sodium channel, voltage-gated (vertebrate): Na_V1.6	26.0 nM		Inhibition by native toxin of human Nav1.6 expressed in HEK-293 cells
Sodium channel, voltage-gated (vertebrate): Na_V1.7	0.3 nM	295.0 pM	Inhibition by native toxin of human Nav1.7 expressed in oocytes
Sodium channel, voltage-gated (vertebrate): Na_V1.8	146.0 nM		Inhibition by native toxin of human Nav1.8 expressed in HEK-293 cells
Sodium channel, voltage-gated (vertebrate): Na_V1.2	41.0 nM		Inhibition by native toxin of human Nav1.2 expressed in HEK-293 cells
Sodium channel, voltage-gated (vertebrate): Na_V1.3	102.0 nM		Inhibition by native toxin of human Nav1.3 expressed in Chinese hamster ovary cells
Calcium channel, voltage-gated (vertebrate): Ca_V3.1	100.0 nM		Inhibition by native toxin of rat Cav3.1 (see ref 8&9)

Taxon	ED50	LD50	PD50	Qualitative Information
Mus musculus				Lethal to rats when injected i.v. at a dose of 1 mg/kg or intrathecally at 0.1 mg/kg

Accessions

Literature References

Original Deposition References
Middleton R.E., Warren V.A., Kraus R.L., Hwang J.C., Liu C.J., Dai G., Brochu R.M., Kohler M.G., Gao Y.-D., Garsky V.M., Bogusky M.J., Mehl J.T., Cohen C.J., Smith M.M. Biochemistry 41:14734-14747(2002). Two tarantula peptides inhibit activation of multiple sodium channels.
Other References
Kraus RL, Warren VA, Smith MM, Middleton RE, Cohen CJ Soc. Neurosci. Abstr. 26:623 (2000) Modulation of α1G and α1C Ca channels by the spider toxin ProTx-II.
Smith J.J., Alphy S., Seibert A.L., Blumenthal K.M. J. Biol. Chem. 280:11127-11133(2005). Differential phospholipid binding by site 3 and site 4 toxins. Implications for structural variability between voltage-sensitive sodium channel domains.
Priest B.T., Blumenthal K.M., Smith J.J., Warren V.A., Smith M.M. Toxicon 49:194-201(2007). ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels.
Smith J.J., Cummins T.R., Alphy S., Blumenthal K.M. J. Biol. Chem. 282:12687-12697 (2007) Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation
Edgerton GB, Blumenthal KM, Hanck DA 2007 Biophysical Society Meeting Abstracts. Biophys. J. Suppl., 21a: Abstract, 2865-Pos Modification of gating kinetics in Cav3.1 by the tarantula toxin ProTxII
Sokolov S., Kraus R.L., Scheuer T., Catterall W.A. Mol. Pharmacol. 73:1020-1028(2008). Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II.
Edgerton G.B., Blumenthal K.M., Hanck D.A. Toxicon 52:489-500 (2008) Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5
Schmalhofer W.A., Calhoun J., Burrows R., Bailey T., Kohler M.G., Weinglass A.B., Kaczorowski G.J., Garcia M.L., Koltzenburg M., Priest B.T. Mol. Pharmacol. 74:1476-1484 (2008) ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors
Edgerton G.B., Blumenthal K.M., Hanck D.A. Toxicon 56:624-36 (2010) Inhibition of the activation pathway of the T-type calcium channel Ca(V)3.1 by ProTxII.

Protein Information

Sequences

Toxin Synonyms

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