Crotamine inhibits preferentially fast-twitching muscles but is inactive on sodium channels.
Crotamine is a peptide toxin from the venom of the rattlesnake Crotalus durissus terrificus that induces a typical hind-limb paralysis of unknown nature. Hind limbs have a predominance of fast-twitching muscles that bear a higher density of sodium channels believed until now to be the primary target of crotamine. Hypothetically, this makes these muscles more sensitive to crotamine and would explain such hind-limb paralysis. To challenge this hypothesis, we performed concentration vs. response curves on fast (extensor digitorum longus (EDL)) and slow (soleus) muscles of adult male rats. Crotamine was tested on various human Na+ channel isoforms (Na(v)1.1-Na(v)1.6 alpha-subunits) expressed in HEK293 cells in patch-clamp experiments, as well as in acutely dissociated dorsal root ganglion (DRG) neurons. Also, the behavioral effects of crotamine intoxication were compared with those of a muscle-selective sodium channel antagonist mu-CgTx-GIIIA, and other sodium-acting toxins such as tetrodotoxin alpha- and beta-pompilidotoxins, sea anemone toxin BcIII, spider toxin Tx2-6. Results pointed out that EDL was more susceptible to crotamine than soleus under direct electrical stimulation. Surprisingly, electrophysiological experiments in human Na(v)1.1 to Na(v)1.6 Na+ channels failed to show any significant change in channel characteristics, in a clear contrast with former studies. DRG neurons did not respond to crotamine. The behavioral effects of the toxins were described in detail and showed remarkable differences. We conclude that, although differences in the physiology of fast and slow muscles may cause the typical crotamine syndrome, sodium channels are not the primary target of crotamine and therefore, the real mechanism of action of this toxin is still unknown.
Rizzi
Carina T
CT
Laboratory of Pharmacology, Instituto Butantan, Av Vital Brasil 1500, Sao Paulo SP-05503-900, Brazil.
Carvalho-de-Souza
João Luís
JL
Schiavon
Emanuele
E
Cassola
Antônio Carlos
AC
Wanke
Enzo
E
Troncone
Lanfranco R P
LR
D000818:Animals; D003435:Crotalid Venoms / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
D003435:Crotalid Venoms; D015222:Sodium Channels; C010563:crotamine