Histrionicotoxins: Roentgen-Ray Analysis of the Novel Allenic and Acetylenic Spiroalkaloids Isolated from a Colombian Frog,
            <i>Dendrobates histrionicus</i>

Daly, John W.; Karle, Isabella L.; Myers, Charles W.; Tokuyama, Takashi; Waters, James A.; Witkop, Bernhard

doi:10.1073/pnas.68.8.1870

Cited by 182 publications

(89 citation statements)

References 11 publications

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“…Nonetheless, the presence of steroids, FFAs, triacylglycerols, and other lipid classes in amphibians attests to the antiquity of these compounds on the tetrapod epidermis. 30,161,162 It is worth noting the occurrence in anurans of glucosylceramides, which are believed to play a role in the water barrier of mammals.…”

Section: Chemical Diversity Revealedmentioning

confidence: 99%

Natural products from the integument of nonavian reptiles

2008

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Section: Chemical Diversity Revealedmentioning

confidence: 99%

Natural products from the integument of nonavian reptiles

2008

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“…Histrionicotoxin (HTX) is a potent toxic compound isolated from the skin of a Columbian frog (17). It behaves in vivo (4,18,19) and in vitro on ACh-receptor-rich membranes (20) in a manner similar, if not identical, to that of a local anesthetic.…”

mentioning

confidence: 99%

Distinct protein components from Torpedo marmorata membranes carry the acetylcholine receptor site and the binding site for local anesthetics and histrionicotoxin.

Sobel¹,

Heidmann²,

Hofler³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

140

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Highly purified subsynaptic membrane fragments prepared from Torpedo marmorata electric organ (specific activity, >4 imol of Na'a nigricoilis a-[3H toxin per mg of protein) exhibit, on sodium dodecyl sulfate/polyacrylamide gel electrophoresis, two major protein bands of apparent molecular weight 40,000 and 43,000, respectively. Dissolution of these membranes by the. nondenaturing detergents Triton X-100 and Berol 043 followed by standard fractionation yielded (j)the 9S acetycholine-receptor protein which still binds the cW4ltoxin and after further purification-yielded, in the presence of sodium dodecyl sulfate, the 40,OOWdalton component, covalently labeled by the affinity reagent 4-(N-maleimido)phenyl[3H]trimethylammonium; only serine was found as the NHrterminal amino acid of this protein; and (iil) a high molecular weight aggregate named 43,000 protein which was resolved in denaturing gels almost exclusively as the 43,000-dalton band. In the absence of detergents, the 43,000 protein binds compounds known to interact with the acetylcholine ionophore: a fluorescent local anesthetic quinacrine and histrionicotoxin (apparent dissociation constant, 7 i 1 x 10-7 M). The regulation of quinacrine fluorescence by carbamylcholine, observed in the intact membrane, no longer occurs with the isolated 43,000 component. The elementary functional unit that accounts for the regulation by acetylcholine (ACh) of cation translocation through an excitable membrane comprises, a priori, two main categories of sites: (i) the ACh receptor site, which binds cholinergic agonists, antagonists (1), and snake venom a-toxins (2); and (ii) a site involved in the selective permeation of small cations. It was further postulated that these two sites were topographically distinct, although coupled by "allosteric" interactions and most likely carried by different polypeptide entities referred to as the ACh-receptor protein sensu stricto, and the ACh ionophore (3) [or ion conductance modulator (4)]. The ACh-receptor protein has been isolated and purified from fish electric organ and skeletal muscle in several laboratories (see ref. 5) on the basis of its ability to bind the snake. a-toxins.Local anesthetics such as prilocaine, tetracaine, and Quotane affect in vwo (6) and in vitro (7) the permeability response to bath-applied ACh in a manner rather different from that of "competitive" antagonists like curare or Flaxedil. These local anesthetics block the response by decreasing the amplitude without changing the apparent dissociation constant for the agonists. When individual current pulses corresponding to single ionophore openings are recorded in the presence of one of these anesthetics, the square contour of the pulse becomes chopped by multiple fast blocking events that are interpreted as representing the repetitive and reversible binding of the local anesthetic directly to the ion gate (E. Neher, personal com-

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“…It has been proposed that histrionicotoxin (HTX), an alkaloid isolated from the skin extracts of the Colombian frog, Dendrobates histrionicus (9), modifies responses to ACh in neuromuscular preparations by interaction with the ion conductance modulator rather than with the ACh receptor (1,(10)(11)(12). HTX and its completely saturated analog, perhydrohistrionicotoxin (H,2-HTX), reduce the amplitude of the end-plate current (EPC) and shorten the half-decay time without altering the equilibrium potential in mammalian and amphibian nerve-muscle preparations.…”

mentioning

confidence: 99%

Perhydrohistrionicotoxin: a potential ligand for the ion conductance modulator of the acetylcholine receptor.

Eldefrawi¹,

Eldefrawi²,

Albuquerque³

et al. 1977

Proc. Natl. Acad. Sci. U.S.A.

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Histrionicotoxin from the Colombian frog Dendrobates histrionicus and its perhydro derivative reversibly block the acetylcholine-sensitive ion conductance system in frog neuromuscular preparations. The perhydro derivative ana [3Hlperhydrohistrionicotoxin, like histrionicotoxin, caused a significant decrease in the peak amplitude of the end-plate current and shortened its rise time and half-decay time. In membrane preparations from Torpedo electroplax, [3Hjperhy-drohistrionicotoxin bound reversibly to a limited number of high-affinity sites [dissociation constant, (KD) = 0.4 ,uMM. The ratio of perhydrohistrionicotoxin to acetylcholine binding sites in these membrane preparations approached 2. Histrionicotoxins, local anesthetics, and certain cholinergic agonists inhibited binding of perhydrohistrionicotoxin. Binding of perhydrohistrionicotoxin to membranes was decreased bylheat or treatment with proteases. Treatment of membranes with Triton X-100 solubilized acetylcholine binding proteins and apparently also perhydrohistrionicotoxin-binding proteins. However, the detergent Triton X-100 also bound [3H perhydrohistrionicotoxin. This nonspecific binding was not saturable and complicated studies on the antagonism by drugs of binding of [3Hjperhydrohistrionicotoxin. In solubilized preparations the binding protein for acetylcholine could be removed by affinity chromatography or immunoprecipitation without affecting binding ofrperhydrohistrionicotoxin. Sephadex chromatography also separated acetylcholine-from perhydrohistrionicotoxinbinding proteins. Perhydrohistrionicotoxin did not bind significantly to purified acetylcholine-receptor protein but presumably bound to an ion conductance modulator protein that was associated with the acetylcholine-receptor in intact membrane and readily separable from the receptor protein after solubilization.The excitatory action of acetylcholine (ACh) at the postsynaptic membrane involves its binding to a specific recognition site followed by activation of the ion conductance modulator (1) and a marked increase in ionic conductance. The ion conductance modulator may represent an ionic channel or ionophore comprising part of the same macromolecule as the ACh receptor or it may be separate from, but somehow coupled with, the receptor. The ACh receptor, purified in several laboratories (2-5), has generally been assumed to contain, as part of the molecule, the ion conductance modulator. However, in no case did the purified ACh receptors, in the presence of lipid membranes, recover the specificity, magnitude, and kinetics of the ion flux or conductance increase characteristic of the intact system (6-8). This may be due either to lack of incorporation of the receptor molecules into the lipid bilayer or to the absence of parts or all of the ion conductance modulator in the purified receptor preparation.It has been proposed that histrionicotoxin (HTX), an alkaloid isolated from the skin extracts of the Colombian frog, Dendrobates histrionicus (9), modifies responses to ACh in neuromusc...

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Histrionicotoxins: Roentgen-Ray Analysis of the Novel Allenic and Acetylenic Spiroalkaloids Isolated from a Colombian Frog, Dendrobates histrionicus

Cited by 182 publications

References 11 publications

Natural products from the integument of nonavian reptiles

Natural products from the integument of nonavian reptiles

Distinct protein components from Torpedo marmorata membranes carry the acetylcholine receptor site and the binding site for local anesthetics and histrionicotoxin.

Perhydrohistrionicotoxin: a potential ligand for the ion conductance modulator of the acetylcholine receptor.

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