Introduction
ProTx II, a 30-amino acid, disulfide-rich peptide toxin, isolated from the venom of the tarantula, Thrixopelma pruriens. This toxin belongs to the inhibitory cysteine knot family and is stabilized by the disulfide frame (C1-C4, C2-C5 and C3-C6). ProTx II has the potency to inhibit the human voltage-gate sodium channel 1.7 (hNa V1.7), which is involved in nociception and might have potential as a pain therapeutic. ProTx-II inhibits Na V1.7 with an IC 50 of 0.3 nM, compared to IC 50s of 30-150 nM for other heterologously expressed Na V1 subtypes.
Biological Activity
ProTx II inhibits current by shifting the voltage dependence of activation to more depolarized potentials. It inhibits multiple sodium channel subtypes but it is reported to be ~100-fold more selective for h Na V1.7. Some studies have pointed out that ProTx-II acts by binding to the membrane-embedded voltage sensor domain of h Na V1.7, but the exact mechanism of action has not been explored clearly. Despite this difference in functional effects, ProTx-II has been proposed to bind to neurotoxin site 4 because it modifies activation. ProTx-II conforms to the inhibitory cystine knot (ICK) 2 motif, a common structural fold among spider toxins targeting ion channels. ICK peptides are defined by a 1-4, 2-5, 3-6 cystine connectivity and often have limited regular secondary structure.
Function
Owing to the well-defined three-dimensional structure and ability to inhibit voltage-gated sodium (Na V), potassium (K V) and calcium (CaV) ion channels with high potency and selectivity, disulfide-rich peptide toxins have attracted much attention as potential analgesics. In addition, voltage-gated sodium channels play important roles in action potential generation and propagation. Among them, Na V1.7 is a crucial contributor to pain sensation, and drugs that selectively target human Na V1.7 (h Na V1.7) could be ideal analgesics. Due to their stability, selectivity and potency, disulfiderich peptides such as ProTx II have been extensively characterized and are vigorously being pursued as drug leads as well as pharmacological tools.
References
1. Schmalhofer, W., Calhoun, J., Burrows, R., Bailey, T., Kohler, M. G., Weinglass, A. B., ... & Priest, B. T. (2008). ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Molecular pharmacology.
2. Henriques, S. T., Deplazes, E., Lawrence, N., Cheneval, O., Chaousis, S., Inserra, M., ... & Craik, D. J. (2016). Interaction of tarantula venom peptide ProTx-II with lipid membranes is a prerequisite for its inhibition of human voltage-gated sodium channel NaV1. 7. Journal of Biological Chemistry, jbc-M116.
3. Xiao, Y., Blumenthal, K. M., Jackson, J. O., Liang, S., & Cummins, T. R. (2010). The tarantula toxins ProTx-II and HWTX-IV differentially interact with human Nav1. 7 voltage-sensors to inhibit channel activation and inactivation. Molecular pharmacology, mol-110.
