Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider.
Rocio K Finol-UrdanetaRebekah ZiegmanZoltan DekanJeffrey R McArthurStewart HeitmannKaren Luna-RamirezHan-Shen TaeAlexander MuellerHana StarobovaYanni K-Y ChinJoshua S WingerdEivind A B UndheimBen Cristofori-ArmstrongAdam P HillVolker HerzigGlenn F KingIrina VetterLachlan D RashDavid J AdamsPaul F AlewoodPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
The King Baboon spider, Pelinobius muticus , is a burrowing African tarantula. Its impressive size and appealing coloration are tempered by reports describing severe localized pain, swelling, itchiness, and muscle cramping after accidental envenomation. Hyperalgesia is the most prominent symptom after bites from P. muticus , but the molecular basis by which the venom induces pain is unknown. Proteotranscriptomic analysis of P. muticus venom uncovered a cysteine-rich peptide, δ/κ-theraphotoxin-Pm1a (δ/κ-TRTX-Pm1a), that elicited nocifensive behavior when injected into mice. In small dorsal root ganglion neurons, synthetic δ/κ-TRTX-Pm1a (sPm1a) induced hyperexcitability by enhancing tetrodotoxin-resistant sodium currents, impairing repolarization and lowering the threshold of action potential firing, consistent with the severe pain associated with envenomation. The molecular mechanism of nociceptor sensitization by sPm1a involves multimodal actions over several ion channel targets, including Na V 1.8, K V 2.1, and tetrodotoxin-sensitive Na V channels. The promiscuous targeting of peptides like δ/κ-TRTX-Pm1a may be an evolutionary adaptation in pain-inducing defensive venoms.
Keyphrases
- neuropathic pain
- chronic pain
- pain management
- particulate matter
- air pollution
- spinal cord
- heavy metals
- polycyclic aromatic hydrocarbons
- spinal cord injury
- type diabetes
- drug induced
- early onset
- water soluble
- skeletal muscle
- risk assessment
- emergency department
- oxidative stress
- endothelial cells
- single molecule
- climate change
- insulin resistance
- postoperative pain
- high fat diet induced
- diabetic rats
- amino acid