title: Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through regulated ATP release.
abstract: Pain-producing animal venoms contain evolutionarily honed toxins that can be exploited to study and manipulate somatosensory and nociceptive signaling pathways. From a functional screen, we have identified a secreted phospholipase A2 (sPLA2)-like protein, BomoTx, from the Brazilian lancehead pit viper (Bothrops moojeni). BomoTx is closely related to a group of Lys49 myotoxins that have been shown to promote ATP release from myotubes through an unknown mechanism. Here we show that BomoTx excites a cohort of sensory neurons via ATP release and consequent activation of P2X2and/or P2X3purinergic receptors. We provide pharmacological and electrophysiological evidence to support pannexin hemichannels as downstream mediators of toxin-evoked ATP release. At the behavioral level, BomoTx elicits nonneurogenic inflammatory pain, thermal hyperalgesia, and mechanical allodynia, of which the latter is completely dependent on purinergic signaling. Thus, we reveal a role of regulated endogenous nucleotide release in nociception and provide a detailed mechanism of a pain-inducing Lys49 myotoxin fromBothropsspecies, which are responsible for the majority of snake-related deaths and injuries in Latin America.
authors.affiliation: Department of Physiology, University of California, San Francisco, CA 94158.
authors.forename: Chuchu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
authors.forename: Katalin F
authors.initials: KF
authors.lastname: Medzihradszky
authors.affiliation: National Natural Toxins Research Center, Texas A&M University-Kingsville, Kingsville, TX 78363.|Department of Chemistry, Texas A&M University-Kingsville, Kingsville, TX 78363.
authors.forename: Elda E
authors.initials: EE
authors.lastname: Sánchez
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94158.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Basbaum
authors.affiliation: Department of Physiology, University of California, San Francisco, CA 94158; david.julius@ucsf.edu.
authors.forename: David
authors.initials: D
authors.lastname: Julius
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017837:Bothrops / Q000235:genetics / Q000502:physiology*; D001938:Brazil; D005260:Female; D054501:Group II Phospholipases A2 / Q000235:genetics / Q000633:toxicity*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010146:Pain / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism; D030162:Reptilian Proteins / Q000235:genetics / Q000633:toxicity*; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D012909:Snake Bites / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D014118:Toxins, Biological / Q000633:toxicity*; D014757:Viper Venoms / Q000201:enzymology* / Q000633:toxicity
chemical_list: D011983:Receptors, Purinergic; D030162:Reptilian Proteins; D014118:Toxins, Biological; D014757:Viper Venoms; D000255:Adenosine Triphosphate; D054501:Group II Phospholipases A2
keywords: ATP release; Lys49 myotoxin; pain; pannexin; purinergic receptor