TY - JOUR T1 - Brevetoxin-3 (PbTx-3) and Its Derivatives Modulate Single Tetrodotoxin-Sensitive Sodium Channels in Rat Sensory Neurons JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 516 LP - 525 VL - 284 IS - 2 AU - G. Jeglitsch AU - K. Rein AU - D. G. Baden AU - D. J. Adams Y1 - 1998/02/01 UR - http://jpet.aspetjournals.org/content/284/2/516.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -