title: Protein toxins of the Echis coloratus viper venom directly activate TRPV1.
abstract: Peptide and protein toxins are essential tools to dissect and probe the biology of their target receptors. Venoms target vital physiological processes to evoke pain. Snake venoms contain various factors with the ability to evoke, enhance and sustain pain sensation. While a number of venom-derived toxins were shown to directly target TRPV1 channels expressed on somatosensory nerve terminals to evoke pain response, such toxins were yet to be identified in snake venoms.
  
  
  
  We screened Echis coloratus saw-scaled viper venom's protein fractions isolated by reversed phase HPLC for their ability to activate TRPV1 channels. To this end, we employed heterologous systems to analyze TRPV1 and NGF pathways by imaging and electrophysiology, combined with molecular biology, biochemical, and pharmacological tools.
  
  
  
  We identified TRPV1 activating proteins in the venom of Echis coloratus that produce a channel-dependent increase in intracellular calcium and outwardly rectifying currents in neurons and heterologous systems. Interestingly, channel activation was not mediated by any of its known toxin binding sites. Moreover, although NGF neurotropic activity was detected in this venom, TRPV1 activation was independent of NGF receptors.
  
  
  
  Echis coloratus venom contains proteins with the ability to directly activate TRPV1. This activity is independent of the NGF pathway and is not mediated by known TRPV1 toxins' binding sites.
  
  
  
  Our results could facilitate the discovery of new toxins targeting TRPV1 to enhance current understanding of this receptor activation mechanism. Furthermore, the findings of this study provide insight into the mechanism through which snakes' venom elicit pain.
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Matan
authors.initials: M
authors.lastname: Geron
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Henry
authors.initials: H
authors.lastname: Matzner
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Lahiani
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Gincberg
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Gadi
authors.initials: G
authors.lastname: Cohen
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors.forename: Philip
authors.initials: P
authors.lastname: Lazarovici
authors.affiliation: Institute for Drug Research (IDR), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel. Electronic address: avip@ekmd.huji.ac.il.
authors.forename: Avi
authors.initials: A
authors.lastname: Priel
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D020932:Nerve Growth Factor / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*; D014118:Toxins, Biological / Q000378:metabolism; D014757:Viper Venoms / Q000378:metabolism*; D017819:Viperidae / Q000378:metabolism*
chemical_list: D011506:Proteins; D017475:Receptors, Nerve Growth Factor; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014118:Toxins, Biological; D014757:Viper Venoms; D020932:Nerve Growth Factor; D002118:Calcium
keywords: Capsaicin; Echis coloratus; HPLC protein fraction; Live-cell calcium imaging; NGF; Pain; Patch clamp technique; TRPV1; Toxins; Viperidae venom