Neurotoxins targetting receptor site 5 of voltage-dependent sodium channels increase the nodal volume of myelinated axons.
The effects of a C57 type ciguatoxin (CTX-3C) and two types of brevetoxins (PbTx-1 and PbTx-3), known to bind to receptor site 5 of the neuronal voltage-dependent Na+ channel-protein, were studied on the morphology of living frog myelinated axons using confocal laser scanning microscopy. During the action of CTX-3C, PbTx-1, and PbTx-3 (10-50 nM), a marked swelling of nodes of Ranvier was observed without apparent modification of internodal parts of axons. In all cases, toxin-induced nodal swelling attained a steady-state within 75-100 min that was well maintained during an additional 90-115 min. The nodal swelling was reversed by an external hyperosmotic solution containing 100 mM D-mannitol and could be completely prevented by blocking voltage-dependent Na+ channels with 1 microM tetrodotoxin. It is suggested that CTX-3C, PbTx-1, and PbTx-3 by activating Na+ channels cause a continuous Na+ entry into axons, increasing internal Na+ concentration. Such an increase directly or indirectly disturbs the osmotic equilibrium between intra- and extra-axonal media, resulting in an influx of water, which is responsible for the long-lasting nodal swelling. Similar results were previously reported with two C60 type ciguatoxins (CTX-1B and CTX-4B). Thus, it is concluded that the four types of toxins targetting receptor site 5 of neuronal voltage-dependent Na+ channels, not only enhance nerve membrane excitability but also, on a long-term basis, cause a marked increase in the axonal volume.
Mattei
C
C
Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS, Gif sur Yvette, France.
Dechraoui
M Y
MY
Molgó
J
J
Meunier
F A
FA
Legrand
A M
AM
Benoit
E
E
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D001665:Binding Sites; D048429:Cell Size / Q000187:drug effects; D002922:Ciguatoxins / Q000494:pharmacology*; D008353:Mannitol / Q000494:pharmacology; D008387:Marine Toxins / Q000494:pharmacology*; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D009498:Neurotoxins / Q000494:pharmacology*; D035964:Oxocins; D011893:Rana esculenta; D011901:Ranvier's Nodes / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000502:physiology*; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D000095702:Polyether Toxins
D002922:Ciguatoxins; D008353:Mannitol; D008387:Marine Toxins; D009498:Neurotoxins; D035964:Oxocins; D015222:Sodium Channels; C082191:ciguatoxin 2; C041017:brevetoxin T17; D000095702:Polyether Toxins; C076262:Brevetoxin A