Nodal swelling produced by ciguatoxin-induced selective activation of sodium channels in myelinated nerve fibers.
Ciguatoxin-1b, the major toxin involved in ciguatera fish poisoning, and D-mannitol were examined on frog nodes of Ranvier using confocal laser scanning microscopy and conventional current- and voltage-clamp techniques. During the action of 10 nM ciguatoxin-1b, an increase in nodal volume was observed as determined by digital image processing and three-dimensional reconstruction of axons. The increase was prevented by blocking Na+ channels with tetrodotoxin. Ciguatoxin-1b (10 nM) induced high frequency action potential discharges up to 70-100 Hz. Analysis of Na+ current revealed that the toxin modified a current fraction which was activated at resting membrane potential and failed to inactivate. Increasing the osmolality of the external solution by about 50% with D-mannitol restored the nodal volume to its control value and suppressed spontaneous action potentials. In addition, D-mannitol affected unmodified and ciguatoxin-1b-treated Na+ currents in a similar manner causing a reduction of maximum conductance, negative shifts of current reversal potential and modification of the voltage-dependence of current activation and inactivation. In conclusion, ciguatoxin-1b induced a tetrodotoxin-sensitive swelling of nodes of Ranvier and selectively affected the Na+ current of myelinated axons. It is proposed that ciguatoxin-1b, by modifying Na+ current, increased intracellular Na+ concentration which caused water influx and nodal swelling. This may explain some of the reported symptoms of ciguatera fish poisoning. D-mannitol, an agent used for ciguatera treatment, was found to reverse the effects of ciguatoxin-1b by reducing Na+ entry and increasing the efflux of water through its osmotic action. It is the first time that osmotic changes produced by the selective activation of ionic channels, i.e. Na+ channels, are reported.
Benoit
E
E
Laboratoire de Physiologie Cellulaire, E.R.S. C.N.R.S., Université de Paris Sud, Orsay, France.
Juzans
P
P
Legrand
A M
AM
Molgo
J
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002922:Ciguatoxins / Q000494:pharmacology*; D008353:Mannitol / Q000494:pharmacology; D018613:Microscopy, Confocal; D009413:Nerve Fibers, Myelinated / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D011893:Rana esculenta; D011901:Ranvier's Nodes / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D012584:Sciatic Nerve / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D012964:Sodium / Q000378:metabolism; D062687:Sodium Channel Agonists; D013779:Tetrodotoxin / Q000494:pharmacology
D062687:Sodium Channel Agonists; D002922:Ciguatoxins; D008353:Mannitol; D013779:Tetrodotoxin; D012964:Sodium