Neurotoxins targetting receptor site 5 of voltage-dependent sodium channels increase the nodal volume of myelinated axons

The effects of a C-57 type ciguatoxin (CTX-3C) and two types of brevetoxins (PbTx-1 and PbTx-3), known to bind to receptor site 5 of the neuronal volt age-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 node s of Ranvier was observed without apparent modification of internodal parts of axons, In all cases, toxin-induced nodal swelling attained a steady-sta te within 75-100 min that was well maintained during an additional 90-115 m in. The nodal swelling was reversed by an external hyperosmotic solution co ntaining 100 mM D-mannitol and could be completely prevented by blocking vo ltage-dependent Naf channels with 1 mu M tetrodotoxin, It is suggested that CTX-3C, PbTx-1, and PbTx-3 by activating Na+ channels cause a continuous N a+ entry into axons, increasing internal Na+ concentration. Such an increas e directly or indirectly disturbs the osmotic equilibrium between intra- an d extra-axonal media, resulting in an influx of water, which is responsible for the long-lasting nodal swelling, Similar results were previously repor ted with two C-60 type ciguatoxins (CTX-IB and CTX-4B), Thus, it is conclud ed that, the four types of toxins targetting receptor site 5 of neuronal vo ltage-dependent Na+ channels, not only enhance nerve membrane excitability but also, on a long-term basis, cause a marked increase in the axonal volum e. (C) 1999 Wiley-Liss, Inc.