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.