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Vol. 284, Issue 2, 516-525, February 1998
Department of Molecular and Cellular Pharmacology, 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 µM 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.
0022-3565/98/2842-0516$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics
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