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Structural highlights

Function

TXPR2_THRPR Blocks both tetrodotoxin-sensitive and tetrodotoxin-resistant human voltage-gated sodium channels by shifting the voltage dependence of channel activation to more positive potentials. Inhibits Nav1.2/SCN2A, Nav1.3/SCN3A, Nav1.5/SCN5A, Nav1.6/SCN8A, Nav1.7/SCN9A, Nav1.8/SCN10A. Is significantly more potent against Nav1.7/SCN9A than the other Nav channel subtypes. Has no significant effect on Kv1.2/KCNA2, Kv1.3/KCNA3, Kv1.5/KCNA5, and Kv2.1/KCNB1 channels. Also inhibits Cav1.2/CACNA1C and Cav3.1/CACNA1G channels with an IC(50) around 100 nM. 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/SCN2A 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. Binds to phospholipids.^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Middleton RE, Warren VA, Kraus RL, Hwang JC, Liu CJ, Dai G, Brochu RM, Kohler MG, Gao YD, Garsky VM, Bogusky MJ, Mehl JT, Cohen CJ, Smith MM. Two tarantula peptides inhibit activation of multiple sodium channels. Biochemistry. 2002 Dec 17;41(50):14734-47. PMID:12475222
2. ↑ Priest BT, Blumenthal KM, Smith JJ, Warren VA, Smith MM. ProTx-I and ProTx-II: gating modifiers of voltage-gated sodium channels. Toxicon. 2007 Feb;49(2):194-201. Epub 2006 Sep 27. PMID:17087985 doi:http://dx.doi.org/10.1016/j.toxicon.2006.09.014
3. ↑ Smith JJ, Cummins TR, Alphy S, Blumenthal KM. Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation. J Biol Chem. 2007 Apr 27;282(17):12687-97. Epub 2007 Mar 5. PMID:17339321 doi:http://dx.doi.org/10.1074/jbc.M610462200
4. ↑ Sokolov S, Kraus RL, Scheuer T, Catterall WA. Inhibition of sodium channel gating by trapping the domain II voltage sensor with protoxin II. Mol Pharmacol. 2008 Mar;73(3):1020-8. Epub 2007 Dec 21. PMID:18156314 doi:http://dx.doi.org/10.1124/mol.107.041046
5. ↑ Edgerton GB, Blumenthal KM, Hanck DA. Evidence for multiple effects of ProTxII on activation gating in Na(V)1.5. Toxicon. 2008 Sep 1;52(3):489-500. Epub 2008 Jul 9. PMID:18657562 doi:http://dx.doi.org/S0041-0101(08)00401-7
6. ↑ Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT. ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol. 2008 Nov;74(5):1476-84. doi: 10.1124/mol.108.047670. Epub 2008 Aug, 26. PMID:18728100 doi:http://dx.doi.org/10.1124/mol.108.047670