title: Isolation and characterization of CvIV4: a pain inducing α-scorpion toxin.
abstract: BACKGROUND
  Among scorpion species, the Buthidae produce the most deadly and painful venoms. However, little is known regarding the venom components that cause pain and their mechanism of action. Using a paw-licking assay (Mus musculus), this study compared the pain-inducing capabilities of venoms from two species of New World scorpion (Centruroides vittatus, C. exilicauda) belonging to the neurotoxin-producing family Buthidae with one species of non-neurotoxin producing scorpion (Vaejovis spinigerus) in the family Vaejovidae. A pain-inducing α-toxin (CvIV4) was isolated from the venom of C. vittatus and tested on five Na(+) channel isoforms.
  
  
  RESULTS
  C. vittatus and C. exilicauda venoms produced significantly more paw licking in Mus than V. spinigerus venom. CvIV4 produced paw licking in Mus equivalent to the effects of whole venom. CvIV4 slowed the fast inactivation of Na(v)1.7, a Na(+) channel expressed in peripheral pain-pathway neurons (nociceptors), but did not affect the Na(v)1.8-based sodium currents of these neurons. CvIV4 also slowed the fast inactivation of Na(v)1.2, Na(v)1.3 and Na(v)1.4. The effects of CvIV4 are similar to Old World α-toxins that target Na(v)1.7 (AahII, BmK MI, LqhIII, OD1), however the primary structure of CvIV4 is not similar to these toxins. Mutant Na(v)1.7 channels (D1586A and E1589Q, DIV S3-S4 linker) reduced but did not abolish the effects of CvIV4.
  
  
  CONCLUSIONS
  This study: 1) agrees with anecdotal evidence suggesting that buthid venom is significantly more painful than non-neurotoxic venom; 2) demonstrates that New World buthids inflict painful stings via toxins that modulate Na(+) channels expressed in nociceptors; 3) reveals that Old and New World buthids employ similar mechanisms to produce pain. Old and New World α-toxins that target Na(v)1.7 have diverged in sequence, but the activity of these toxins is similar. Pain-inducing toxins may have evolved in a common ancestor. Alternatively, these toxins may be the product of convergent evolution.
authors: Section of Neurobiology, University of Texas at Austin, Austin, Texas, United States of America. ahrowe@mail.utexas.edu
authors: Ashlee H
authors: AH
authors: Rowe
authors: Yucheng
authors: Y
authors: Xiao
authors: Joseph
authors: J
authors: Scales
authors: Klaus D
authors: KD
authors: Linse
authors: Matthew P
authors: MP
authors: Rowe
authors: Theodore R
authors: TR
authors: Cummins
authors: Harold H
authors: HH
authors: Zakon
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects; D005591:Chemical Fractionation; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D010146:Pain / Q000139:chemically induced / Q000473:pathology*; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012604:Scorpion Venoms / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification* / Q000633:toxicity*; D012605:Scorpions / Q000737:chemistry*; D020539:Sequence Analysis, Protein; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism
chemical_list: D000596:Amino Acids; C035413:Centruroides toxin; D018076:DNA, Complementary; D010455:Peptides; D020033:Protein Isoforms; D012333:RNA, Messenger; D012604:Scorpion Venoms; D015222:Sodium Channels