RhTx is a smallpeptide toxin fromScolopendra subspinipes mutilans, also called the Chinese red-headed centipede. RhTx binds to the outer pore region of the temperature regulatedTRPV1 ion channel, preferably in activated state, causing a downwards shift in the activation threshold temperature, which leads to the immediate onset ofheat pain.[1]
RhTx is a smallpeptide toxin, with a compact 3D-structure. The gene encoding for RhTx translates into a 69amino acid peptide that shows no homology to any known animal toxin. This peptide, after post- translational modifications, yields a mature toxin of 27 amino acids. RhTx has two pairs ofdisulfide bonds. While theN-terminus of the peptide contains no charged amino acids, theC-terminus of the peptide is rich in charged amino acids. In the folded peptide, these charged amino acids are all located on the same side of the peptide, making RhTx a polar molecule.[1]
RhTx binds to the outer pore region of thepolymodalTRPV1 ion channel. The toxin preferably binds to TRPV1 in the activated state of the channel. RhTx has a high affinity for the TRPV1 ion channel, which results in very rapid binding and slow unbinding. The TRPV1 channel is a non-selectivecation channel, with a highpermeability to Ca2+.[2]TRPV1 is mainly expressed in sensory neurons and can be activated by different stimuli, including high temperatures (heat), acids, pollutants with negative electric charge and endogenous metabolites such asanandamide.[3] The channel is also targeted by the active component of chilli pepperscapsaicin, and the spider toxinsVanillotoxin and DkTx.[3][4][5]
After binding to the outer pore region of the TRPV1, RhTx can interact with both the turret and the pore helix through electrostatic andhydrophobic interactions. RhTx binding is expected to induce conformational changes to the outer pore, which are thought to be the cause of the drop of the activation threshold for the TRPV1 channel. These changes strongly promote the opening of the TRPV1 channel at the normal body temperature of the organism, resulting in intense burning pain.[1]It is hypothesized that RhTx binding might also interfere with ion permeation due to its interaction with the pore helix.[1]
In mice, injections of RhTx induced pain behavior, which was distinct from pain behavior mediated byinflammation, but similar to the behavior elicited bycapsaicin injection. Injections in mice also caused a rapid drop of core body temperature at normal conditions, by less than 1 degree Celsius. TheEC50 in mice is estimated to be 500 nM.[1]While the effect of isolated RhTx administration is not known in humans, bites of theS. subspinipes mutilans species generally cause immediate localized burning pain, followed byedema,erythema and other localized symptoms.[6] Seriousmorbidity is very uncommon and treatment is supportive, focusing on treating symptoms.[6]
^Caterina, M. J., & Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annual review of neuroscience, 24(1), 487-517.doi:10.1146/annurev.neuro.24.1.487PMID11283319
^abCortright, D. N. and Szallasi, A. (2004). Biochemical pharmacology of the vanilloid receptor TRPV1. European Journal of Biochemistry, 271: 1814–1819.doi:10.1111/j.1432-1033.2004.04082.xPMID15128291
^Siemens, J., Zhou, S., Piskorowski, R., Nikai, T., Lumpkin, E. A., Basbaum, A. I., ... & Julius, D. (2006). Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature, 444(7116), 208-212.doi:10.1038/nature05285PMID17093448
^Bohlen, C. J., Priel, A., Zhou, S., King, D., Siemens, J., & Julius, D. (2010). A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell, 141(5), 834-845.doi:10.1016/j.cell.2010.03.052PMID20510930
^abFenderson, J. L. (2014). Centipede Envenomation: Bringing the Pain to Hawai ‘i and Pacific Islands. Hawai'i Journal of Medicine & Public Health, 73(11 Suppl 2), 41.PMID25478303
