RhTx is a small
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
toxin from
''Scolopendra subspinipes mutilans'', also called the Chinese red-headed centipede. RhTx binds to the outer pore region of the temperature regulated
TRPV1
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 th ...
ion channel, preferably in activated state, causing a downwards shift in the activation threshold temperature, which leads to the immediate onset of
heat pain.
[
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. . ]
Sources
RhTx is a component of the venom of the
''S. subspinipes mutilans'', also called the Chinese red-headed centipede.
[
]
Chemistry
RhTx is a small peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
toxin, with a compact 3D-structure. The gene encoding for RhTx translates into a 69 amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
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
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
. 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.[
]
Target
RhTx binds to the outer pore region of the polymodal TRPV1
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 th ...
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+.[Caterina, M. J., & Julius, D. (2001). The vanilloid receptor: a molecular gateway to the pain pathway. Annual review of neuroscience, 24(1), 487-517. ]
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
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid r ...
.[Cortright, D. N. and Szallasi, A. (2004). Biochemical pharmacology of the vanilloid receptor TRPV1. European Journal of Biochemistry, 271: 1814–1819.
] The channel is also targeted by the active component of chilli peppers capsaicin
Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burnin ...
, and the spider toxins Vanillotoxin
Vanillotoxins (VaTxs, subtypes VaTx1, VaTx2, and VaTx3) 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), activati ...
and DkTx.[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. ]
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
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
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.[
It is hypothesized that RhTx binding might also interfere with ion permeation due to its interaction with the pore helix.][
]
Toxicity
In mice, injections of RhTx induced pain behavior, which was distinct from pain behavior mediated by inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
, but similar to the behavior elicited by capsaicin
Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus ''Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burnin ...
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.[
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
Erythema (from the Greek , meaning red) is redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection, or inflammation. Examples of erythema not asso ...
and other localized symptoms.[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. ] Serious morbidity
A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
is very uncommon and treatment is supportive, focusing on treating symptoms.[
]
References
{{Transient receptor potential channel modulators
Ion channel toxins
Centipede toxins