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      Brevetoxin-3 (PbTx-3) and its derivatives modulate single tetrodotoxin-sensitive sodium channels in rat sensory neurons.

      The Journal of pharmacology and experimental therapeutics

      Animals, Animals, Newborn, Dinoflagellida, Ion Channel Gating, drug effects, Marine Toxins, pharmacology, Membrane Potentials, Neuromuscular Blocking Agents, Nodose Ganglion, Oxocins, Patch-Clamp Techniques, Rats, Sodium Channels, Structure-Activity Relationship

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          Brevetoxin-3 (PbTx-3), produced by marine dinoflagellates (Ptychodiscus brevis), is a lipophilic 11-ring polyether molecule that binds with high affinity to site 5 of the voltage-sensitive sodium (Na+) channel. The effects of PbTx-3 and its derivatives were studied in cell-attached membrane patches on neurons dissociated from neonatal rat nodose ganglia by the patch-clamp technique. PbTx-3 (30-500 nM) produced a shift in activation to more negative membrane potentials whereby single-channel activity was observed under steady-state conditions (maintained depolarization at -50 mV). The unitary current-voltage relationship is linear, which exhibits a reversal potential of approximately +60 mV. Two unitary current amplitudes could be observed in the presence of PbTx-3, with slope conductances of 10.7 pS and 21.2 pS. PbTx-3 inhibits the inactivation of Na+ channels and prolongs the mean open time of these channels. Unitary Na+ currents could be blocked by 1 microM tetrodotoxin (TTX) added to the pipette solution, which indicates that the single-channel currents are caused by the opening of TTX-sensitive Na+ channels. The PbTx-3 molecule is proposed to have multiple active centers (A-ring lactone, C-42 of R side chain) interacting with the Na+ channel binding site. Modification of the molecular structure of PbTx-3 at these centers produced derivatives (PbTx-6, 2,3,41,43-tetrahydro-PbTx-3, 2,3,27,28,41, 43-hexahydro-PbTx-3 and 2,3-dihydro-PbTx-3 A-ring diol), which were less potent than PbTx-3 in producing similar effects on Na+ channel kinetics. PbTx-3 and its derivatives may provide insight into the mechanics of voltage-sensitive Na+ channel gating.

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