Batrachotoxins actions

Batrachotoxin at present remains an important, indeed often essential, tool for mechanistic studies of the function of voltage-dependent sodium channels and for the investigation of the role of depolarization and/or influx of sodium ions on physiological functions. Batrachotoxin has been particularly useful in the study of the function of sodium channels, purified and reconstituted into artificial lipid bilayers. A summary and overview of the extensive studies with batrachotoxin appeared in 1986 (5). Since that time more than 100 articles dealing with the activity of batrachotoxin and/ or the radioligand batrachotoxinin A 20a-[ H]benzoate have appeared, and it is beyond the scope of the present review to summarize this extensive recent literature. A few selected developments are as follows allosteric enhancement of the action of batrachotoxins by pyrethroid insecticides... 

Batrachotoxin is an important research tool because of its action of holding voltage-gated sodium channels open as well as its specific effects at other ligandbinding sites. It was previously used commonly in channel and ligand research. There are no commercially available stocks of batrachotoxins, however, and work in Colombia is currently difficult or impossible, so these chemicals are used less frequently in research. 

Daly JW, Myers CW, Warnick JE, and Albuquerque EX (1980) Eevels of batrachotoxin and lack of sensitivity to its action in poison-dart frogs Phyllobates). Science 208 1383-1385. 

IV) ANTIARRHYTHMIC. It is a SMOOTH MUSCLE RELAXANT and coronary VASODILATOR. It can be used as an antihypertensive and antianginal. and in antimigraine prophylaxis, verapamil hydrochloride verapamil, veratridine is an alkaloid from Schoenocaulon officinale (Liliaceae), and is a neurotoxin and sodium-Channel ACTIVATOR that binds to Na -channels, leading to depolarization. It has similar but weaker actions to batrachotoxin. Vercyte pipobroman. 

Castillo C, Villegas R, Recio-Pinto E (1992) Alkaloid-modified sodium channels from lobster walking leg nerves in planar lipid bilayers. J Gen Physiol 99 897-930 Castillo C, Piemavieja C, Recio-Pinto E (1996) Interactions between anemone toxin II and veratridine on single neuronal sodium channels. Brain Res 733 243-252 Catterall WA (1975a) Activation of the action potential Na ionophore of cultured neuroblastoma cells by veratridine and batrachotoxin. J Biol Chem 250 4053-4059 Catterall WA (1975b) Cooperative activation of action potential Na ionophore by neurotoxins. Proc Natl Acad Sci USA 72 1782-1786 Catterall WA (1977) Activation of the action potential Na ionophore by neurotoxins. 

Crosby DG (1971) Minor insecticides of plant origin. In Jacobson MJ, Crosby DG (eds) Naturally occurring insecticides. Dekker, New York, pp 177-239 Cukierman S (1991) Inactivation modifiers of Na currents and the gating of rat brain Na channels in planar lipid membranes. Pfliigers Arch 419 514-521 Daly JW, Myers CW, Warnick JE, Albuquerque EX (1980) Levels of batrachotoxin and lack of sensitivity to its action in poison-dart frogs (Phyllobates). Science 208 1383-1385... 

Tetrodotoxin and saxitoxin, which block the voltage-dependent sodium channels, prevent and actually reverse batrachotoxin-elicited depolarizations. The blockade by tetrodotoxin occurs at a different channel site than that at which batrachotoxin acts. Classical anesthetics, however, would appear to antagonize the action of batrachotoxin through competition for the binding site (50 and references therein). Local anesthetics have been shown to block but perhaps not reverse the action of batrachotoxin in squid axon (79), rat diaphragm (77), eel electroplax (55), frog nerve 160, 765), synaptosomes (706, 179), and neuroblastoma cells (50, 755, 756). 

Batrachotoxin will not cause depolarization in the absence of sodium ions, consonant with its proposed mechanism of action. In denervated muscle, sodium channels develop which are not sensitive to tetrodotoxin but do retain sensitivity to batrachotoxin (8). Batrachotoxin causes a massive release of acetylcholine in neuromuscular preparations. This effect, undoubtedly due to depolarization of the presynaptic terminal, is prevented by tetrodotoxin (25, 149, 269) or by botulinus toxin (236). 

Pretreatment of lobster axons with sulfhydryl reagents such as / -chloromercuribenzene sulphonic acid and dithiothreitol prevent or reduce respectively depolarization elicited by batrachotoxin (77). Such treatment does not prevent stimulus-evoked activation of sodium channels. The results with such sulfhydryl reagents provides evidence for the importance of a protein to the action of batrachotoxin. 

Batrachotoxin has no effect on a calcium channel (18), or on potassium channels (795). However, batrachotoxin does appear to antagonize the increase in conductance elicited by nicotinic agonists in striated neuromuscular preparations (111) and adrenal glands (164, 165). The mechanism involved in inhibition of nicotinic receptor-controlled conductances by batrachotoxin remains unclear but actually might represent another site of action for the alkaloid. Batrachotoxin, however, has no effect on binding of a-bungarotoxin or histrionicotoxin to the acetylcholine receptor-channel... 

Batrachotoxin is an extremely potent cardiotonic agent 129,132,133, 156,183,233). Its actions lead ultimately to arrhythmias and cardiac arrest. The basis for the action of batrachotoxin in cardiac preparations is linked to activation of sodium channels and can be antagonized by tetrodotoxin. Unlike the cardiotonic cardiac glycosides, batrachotoxin has little effect on Na -K -ATPase, causing only a slight inhibition of the enzyme at a concentration (60 pM) much higher than that usually employed for depolarization of cells (79). 

Batrachotoxin was most effective in neuromuscular preparations at pH 9, at which pH much of the alkaloid would be in the unionized form (268). It also has been suggested that a membrane constituent ionized at pH values >6.0 is essential to the action of batrachotoxin (5). Binding studies support this interpretation (45, vide infra). Obviously, further research is required to define the active form of batrachotoxin and the nature of its binding site. 

Activation of the action potential Na ionophore of cultured neuroblastoma cells by veratridine and batrachotoxin. J. Biol. Chem. 250, 4053—4059 (1975). 

Khodorov, B. I., E. M. Peganov, S. V. Revenko, and L. D. Shishkova Sodium currents in voltage clamped nerve fiber of frog under the combined action of batrachotoxin and procaine. Brain Res. 84, 541—546 (1975). 

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