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Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):E2524-E2532. doi: 10.1073/pnas.1615484114. Epub 2017 Mar 6.

Lys49 myotoxin from the Brazilian lancehead pit viper elicits pain through regulated ATP release.

Author information

1
Department of Physiology, University of California, San Francisco, CA 94158.
2
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
3
National Natural Toxins Research Center, Texas A&M University-Kingsville, Kingsville, TX 78363.
4
Department of Chemistry, Texas A&M University-Kingsville, Kingsville, TX 78363.
5
Department of Anatomy, University of California, San Francisco, CA 94158.
6
Department of Physiology, University of California, San Francisco, CA 94158; david.julius@ucsf.edu.

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 P2X2 and/or P2X3 purinergic 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 from Bothrops species, which are responsible for the majority of snake-related deaths and injuries in Latin America.

KEYWORDS:

ATP release; Lys49 myotoxin; pain; pannexin; purinergic receptor

PMID:
28265084
PMCID:
PMC5373363
DOI:
10.1073/pnas.1615484114
[Indexed for MEDLINE]
Free PMC Article

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