Brevetoxin derivatives that inhibit toxin activity

Background: The brevetoxins are marine neurotoxins that interfere with the normal functions of the voltage-gated Na + channel. We have identified two brevetoxin derivatives that do not exhibit pharmacological properties typical of the brevetoxins and that function as brevetoxin antagonists. Results: PbTx-3 and benzoyl-PbTx-3 elicited Na + channel openings during steady-state depolarizations; however, two PbTx-3 derivatives retained their ability to bind to the receptor, but did not elicit Na + channel openings. α-Naphthoyl-PbTx-3 acted as a PbTx-3 antagonist but did not affect Na + channels that were not exposed to PbTx-3. β-Naphthoyl-PbTx-3 reduced openings of Na + channels that were not exposed to PbTx-3. Conclusions: Some modifications to the brevetoxin molecule do not alter either the binding properties or the activity of these toxins. Larger modifications to the K-ring sidechain do not interfere with binding but have profound effects on their pharmacological properties. This implies a critical function for the K-ring sidechain of the native toxin

The gut of the juvenile African lungfish Protopterus annectens: A light and scanning electron microscope study

10.1002/jmor.10952Journal of Morphology2727769-779JOMO

Ciguatoxin-induced oscillations in membrane potential and action potential firing in rat parasympathetic neurons

The actions of ciguatoxins from the Pacific (P-CTX-1) and Caribbean (C-CTX-1) regions were investigated in isolated parasympathetic neurons from rat intracardiac ganglia using patch-clamp recording techniques. Under current-clamp conditions, bath application of P-CTX-1 (1–10 nm) or C-CTX-1 (10–30 nm) caused a gradual depolarization that was accompanied by oscillation of the membrane potential leading to tonic action potential firing. Membrane potential oscillations were observed between −45 and −60 mV and had an amplitude of 10–20 mV and a mean frequency of 10 Hz. Oscillation frequency was temperature-dependent with a Q10 of 2.0. Membrane oscillations were temporarily inhibited by hyperpolarizing current pulses and potentiated by weak depolarizing current pulses. The amplitude of oscillations was reduced upon lowering the external Na+ concentration and inhibited by tetrodotoxin (TTX), tetracaine or Zn2+. Tetraethylammonium, 4-aminopyridine, Cs+, Cd2+, Ba2+, 1,4,4'-diothiocyanato-2,2'-stilbenedisulphonic acid (DIDS) and ouabain had no effect on the CTX-1-induced membrane depolarization and oscillations. Brevetoxin (PbTx-3, 100 nm), in contrast to CTX-1, caused a membrane depolarization that was not associated with oscillation of the membrane potential. Under voltage-clamp conditions, P-CTX-1 inhibited the peak amplitude of the voltage-dependent Na+ current and shifted the activation curve to more negative potentials, but membrane oscillations were not seen in this configuration. These results suggest that ciguatoxins cause oscillation of the membrane potential in mammalian autonomic neurons by modifying the activation and inactivation properties of a population of TTX-sensitive Na+ channels