Receptor brevetoxin

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

After initial experiments demonstrating that the antiserum was capable of completely inhibiting the binding of [ H]PbTx-3 to its receptor site in rat brain membranes (Figure 9), we began studies designed to evaluate potential of the antiserum for prophylaxis and treatment of brevetoxin intoxication (34). The tethered rat model was used, and surgical implantations were identical to those described above. Heart rate, core and peripheral body temperatures, lead VIO ECG, and arterial blood pressure were monitored continuously. Respiratory rate was recorded each 5 min for the first 3 hr, then each 15 min until 6 hr. 

This chapter summarizes recent work on the molecular basis of the toxic actions of ciguatoxin and brevetoxins. It is shown (i) that the molecular target for these toxins is the voltage-dependent Na channel of excitable tissues arid (ii) that ciguatoxin and brevetoxins share a common receptor site on the Na channel. 

Figure 2.3. The brevenals are shorter transfused polyether molecules isolated from K. brevis. Consisting of a 6-7-6-7-7 ring motif, these materials bind with high affinity in brevetoxin receptor assays, and effectively act as inhibitors of brevetoxin binding and activity. Brevenal is the major constituent derived from cultures or the environment, with smaller amounts of brevenol (brevenal with the aldehyde reduced to the alcohol) (Baden et al. 2005).

Catterall WA, Coppersmith J (1981) Pharmacological properties of sodium channels in cultured rat heart cells. Mol Pharmacol 20 533-542 Catterall WA, Gainer M (1985) Interaction of brevetoxin A with a new receptor site on the sodium channel. Toxicon 23 497-504... 

Bourdelais, A.J., Campbell, S., Jacocks, H., Naar, J., Wright, J.L.C., Carsi, J., and Baden, D.G. Brevenal is a natural inhibitor of brevetoxin in sodium channel receptor binding assays. Cell. Mol. Neurobiol., 24, 553-563, 2004b. 

Definitive evidence supporting the presence of a receptor would include classic binding studies, which due to scarcity of MTX are difficult to conduct. Nevertheless, if MTX acts like most known nonpeptide marine toxins, one would expect a receptor. For instance, toxins with structural similarities to MTX, like brevetoxins and palytoxin (PTX) have recognized receptors [46-49]. The case of PTX is of particular interest, since it shares some of its cellular effects with MTX, such as membrane depolarization, [Ca i increases and oncotic cell death [50]. 

Washburn, B. S., Rein, K. S., Baden, D. G. et al., Brevetoxin-6 (PbTx-6), a nonaromatic marine neurotoxin, is a ligand of the aryl hydrocarbon receptor. Arch. Biochem. Biophys. 343, 149, 1997. 

Lombet, A., Bidard, J. N., and Lazdunski, M., Ciguatoxin and brevetoxins share a common receptor site on the neuronal voltage-dependent Na-l- channel, FEBS Lett. 219, 355, 1987. 

Trainer, V. L., Baden, D. G., and Catterall, W. A., Identification of peptide components of the brevetoxin receptor site of rat brain sodium channels, J. Biol. Chem. 269, 19904, 1994. 

Dravid, S. M., Baden, D. G., and Murray, T. F., Brevetoxin augments NMDA receptor signaling in murine neocortical nenrons. Brain Res. 1031, 30, 2005. 

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