RhTx

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RhTx is a small peptide toxin from Scolopendra subspinipes mutilans, also called the Chinese red-headed centipede. RhTx binds to the outer pore region of the temperature regulated TRPV1 ion channel, preferably in activated state, causing a downwards shift in the activation threshold temperature, which leads to the immediate onset of heat pain. [1]

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RhTx is a component of the venom of the S. subspinipes mutilans, also called the Chinese red-headed centipede. [1]

Chemistry

RhTx is a small peptide toxin, with a compact 3D-structure. The gene encoding for RhTx translates into a 69 amino 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 of disulfide bonds. While the N-terminus of the peptide contains no charged amino acids, the C-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]

Target

RhTx binds to the outer pore region of the polymodal TRPV1 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-selective cation channel, with a high permeability 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 as anandamide. [3] The channel is also targeted by the active component of chilli peppers capsaicin, and the spider toxins Vanillotoxin and DkTx. [3] [4] [5]

Mode of action

After binding to the outer pore region of the TRPV1, RhTx can interact with both the turret and the pore helix through electrostatic and hydrophobic 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]

Toxicity

In mice, injections of RhTx induced pain behavior, which was distinct from pain behavior mediated by inflammation, but similar to the behavior elicited by capsaicin injection. Injections in mice also caused a rapid drop of core body temperature at normal conditions, by less than 1 degree Celsius. The EC50 in mice is estimated to be 500 nM. [1] While the effect of isolated RhTx administration is not known in humans, bites of the S. subspinipes mutilans species generally cause immediate localized burning pain, followed by edema, erythema and other localized symptoms. [6] Serious morbidity is very uncommon and treatment is supportive, focusing on treating symptoms. [6]

Related Research Articles

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of tastes, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

<span class="mw-page-title-main">TRPV1</span> Receptor responsible for regulation of body temperature

The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels.

<span class="mw-page-title-main">TRPV</span> Subgroup of TRP cation channels named after the vanilloid receptor

TRPV is a family of transient receptor potential cation channels in animals. All TRPVs are highly calcium selective.

<span class="mw-page-title-main">Capsazepine</span> Chemical compound

Capsazepine is a synthetic antagonist of capsaicin. It is used as a biochemical tool in the study of TRPV ion channels.

AG 489 is a component of the venom produced by Agelenopsis aperta, a North American funnel web spider. It inhibits the ligand gated ion channel TRPV1 through a pore blocking mechanism.

<span class="mw-page-title-main">TRPA1</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 gene.

<span class="mw-page-title-main">TRPV2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily V member 2 is a protein that in humans is encoded by the TRPV2 gene. TRPV2 is a nonspecific cation channel that is a part of the TRP channel family. This channel allows the cell to communicate with its extracellular environment through the transfer of ions, and responds to noxious temperatures greater than 52 °C. It has a structure similar to that of potassium channels, and has similar functions throughout multiple species; recent research has also shown multiple interactions in the human body.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<span class="mw-page-title-main">TRPV3</span>

Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.

<span class="mw-page-title-main">Apamin</span> Chemical compound

Apamin is an 18 amino acid globular peptide neurotoxin found in apitoxin (bee venom). Dry bee venom consists of 2–3% of apamin. Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous system. Toxicity is caused by only a few amino acids, in particular cysteine1, lysine4, arginine13, arginine14 and histidine18. These amino acids are involved in the binding of apamin to the Ca2+-activated K+ channel. Due to its specificity for SK channels, apamin is used as a drug in biomedical research to study the electrical properties of SK channels and their role in the afterhyperpolarizations occurring immediately following an action potential.

<span class="mw-page-title-main">Iodoresiniferatoxin</span> Chemical compound

Iodoresiniferatoxin (I-RTX) is a strong competitive antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. I-RTX is derived from resiniferatoxin (RTX).

Relief from chronic pain remains a recognized unmet medical need. Consequently, the search for new analgesic agents is being intensively studied by the pharmaceutical industry. The TRPV1 receptor is an ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990, since then development of novel TRPV1 antagonists has come a long way. This effort has led to the identification of several TRPV1 antagonists that have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain then this class of compounds may offer one of the first novel mechanisms for the treatment of pain, in many years.

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. It is applied three times daily for a maximum of three months. Zucapsaicin is a member of phenols and a member of methoxybenzenes It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1 that reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use.

BeKm-1 is a toxin from the Central Asian scorpion Buthus eupeus. BeKm-1 acts by selectively inhibiting the human Ether-à-go-go Related Gene (hERG) channels, which are voltage gated potassium ion channels.

<span class="mw-page-title-main">Vanillotoxin</span> Chemical compound

Vanillotoxins are neurotoxins found in the venom of the tarantula Psalmopoeus cambridgei. They act as agonists for the transient receptor potential cation channel subfamily V member 1 (TRPV1), activating the pain sensory system. VaTx1 and 2 also act as antagonists for the Kv2-type voltage-gated potassium channel (Kv2), inducing paralytic behavior in small animals.

Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula. The toxin is mostly known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation threshold.

<span class="mw-page-title-main">Mambalgins</span>

Mambalgins are peptides found in the venom of the black mamba, an elapid snake. Mambalgins are members of the three-finger toxin (3FTx) protein family and have the characteristic three-finger protein fold. First reported by French researchers in 2012, mambalgins are unusual members of the 3FTx family in that they have the in vivo effect of causing analgesia without apparent toxicity. Their mechanism of action is potent inhibition of acid-sensing ion channels.

Tamulotoxin is a venomous neurotoxin from the Indian Red Scorpion.

Ssm6a, or μ-SLPTX-Ssm6a, is a toxin from the venom of the Chinese red-headed centipede. It has strong analgesic properties, probably owing to its strong inhibitory effects on Nav1.7 channels.

U7-ctenitoxin-Pn1a (or U7-CNTX-Pn1a for short) is a neurotoxin that blocks TRPV1 channels, and can exhibit analgestic effects. It is naturally found in the venom of Phoneutria nigriventer.

References

  1. 1 2 3 4 5 6 Yang, S., Yang, F., Wei, N., Hong, J., Li, B., Luo, L., ... & Lai, R. (2015). A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. Nature Communications, 6. doi : 10.1038/ncomms9297. PMID   26420335
  2. ↑ 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.24.1.487 PMID   11283319
  3. 1 2 Cortright, 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.x PMID   15128291
  4. ↑ 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/nature05285 PMID   17093448
  5. ↑ 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.2010.03.052 PMID   20510930
  6. 1 2 Fenderson, 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. PMID   25478303
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