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Binding of Saxitoxin to Electrically Excitable Neuroblastoma Cells (Ion Transport/Scorpion Toxin/Batrachotoxin) WILLIAM A

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Binding of Saxitoxin to Electrically Excitable Neuroblastoma Cells (Ion Transport/Scorpion Toxin/Batrachotoxin) WILLIAM A Proc. Natl. Acad. Sci. USA Vol. 75, No. 1, pp. 218-222, January 1978 Biochemistry Binding of saxitoxin to electrically excitable neuroblastoma cells (ion transport/scorpion toxin/batrachotoxin) WILLIAM A. CATTERALL* AND CYNTHIA S. MORROW* Laboratory of Biochemical Genetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20014 Communicated by Bernhard Witkop, November 1, 1977 ABSTRACT Saxitoxin inhibits the action potential Na+ permeability by 22Na+ influx (9), and measurement of scorpion ionophore of electrically excitable neuroblastoma cells with a toxin binding (11) have been described in detail. Scorpion toxin KI of 3.7 nM. Binding experiments detect a single class of sat- was purified by ion exchange chromatography and appeared urable binding sites with KD = 3.9 nM and a binding capacity of 156 fmol/mg of cell protein (78 sites per ,.m2 of cell surface). to be homogeneous in gel electrophoresis and isoelectric fo- Saturable binding is completely inhibited by tetrodotoxin but cusing experiments (9). The purified toxin was iodinated in a is unaffected by scorpion toxin or batrachotoxin. No saturable lactoperoxidase-catalyzed reaction and the labeled derivatives binding is observed in cultures of clone N103, a variant neuro- were separated by ion exchange chromatography (11). Unla- blastoma clone lacking the action potential Na+ response. Thus, beled, monoiodo and diiodo derivatives are separated by this saxitoxin binds specifically to the action potential Na+ iono- phore in neuroblastoma cells. Comparison of saxitoxin and technique. Only diiodo scorpion toxin was used in these studies. scorpion toxin binding reveals that there are three saxitoxin Because the preparations used contained only diiodo scorpion receptor sites for each scorpion toxin receptor site. The impli- toxin and no contaminating species, the specific radioactivity cations of this stoichiometry are considered. was exactly twice that of the sodium iodide (125I + 127I) used in the reaction and therefore was known with good accura- The heterocyclic neurotoxins, saxitoxin and tetrodotoxin, are cy. specific inhibitors of the action potential Na+ ionophore of Preparation and Characterization of [3HJSaxitoxin. Saxi- nerve axons (1, 2) and cultured neuroblastoma cells (3). These toxin was kindly supplied by E. J. Schantz, University of Wis- toxins bind specifically to axonal membranes at sites associated consin. [3H]Saxitoxin was prepared by the specific [3H]H20 with the action potential Na+ ionophore (4-6). The density and exchange procedure of Ritchie et al. (4). Dry saxitoxin (1.85 mg) some of the properties of these receptor sites have been de- was dissolved in [3H]H20 (25 Ci) and incubated at 500 for 3 hr. scribed. Labile 3H was removed in vacuo with H20 rinses at 0°. (These Purified polypeptide toxins from scorpion venom inhibit operations were performed by New England Nuclear Corp.) inactivation of the action potential Na+ ionophore in voltage Aliquots of this material were then purified by high-voltage clamp experiments on nerve axons (7, 8)t and act cooperatively paper electrophoresis as described by Ritchie et al. (4). Fractions with grayanotoxin and the alkaloids batrachotoxin, veratridine, from the electrophoretogram were tested for saxitoxin biologic and aconitine to cause persistent activation of the Na+ iono- activity and for [3H]saxitoxin. The concentration of saxitoxin phore (9). lodinated derivatives of scorpion toxin retain full in each fraction was determined by comparing the inhibition biologic activity (10, 11). These derivatives bind specifically of the action potential Na+ ionophore by [3H]saxitoxin fractions to action potential Na+ ionophores in electrically excitable and by standard saxitoxin solutions of known concentration as neuroblastoma cells (10, 11). Studies of scorpion toxin binding, illustrated in Fig. 1. A standard saxitoxin solution obtained from activation of the Na+ ionophore by scorpion toxin and alkaloid the U.S. Food and Drug Administration and a standard saxitoxin toxins, and inhibition of the Na+ ionophore by tetrodotoxin and solution prepared from dry saxitoxin in our laboratory gave saxitoxin have led to the hypothesis that the action potential Na+ identical results. ionophore contains three distinct receptor sites for neurotoxins The radiochemical purity of [3H]saxitoxin was determined (11, 12). One of these sites is specific for the polypeptide scor- by using the method of Levinson and Meves (5) and of Ritchie pion toxin and is involved in inactivation of the Na+ ionophore. et al. (4). This method depends on the capacity of excitable A second receptor site interacts specifically with the alkaloid tissue to bind native saxitoxin specifically. Freshly dissected rat toxins to cause persistent activation of the Na+ ionophore. Te- brains were homogenized in 0.25 M sucrose (10 ml/g wet trodotoxin and saxitoxin bind at a third receptor site which may weight). A membrane fraction was obtained by centrifugation be located within the transmembrane Na+ channel itself at 40,000 X gfor 15 min and was resuspended at a concentra- (13). tion of 0.4 g original wet weight/ml in the medium used for In this report, we describe the density, specificity, and saxitoxin binding assays (see below). Purified [3H]saxitoxin binding characteristics of the receptor sites for saxitoxin in (approximately 3 nM) was incubated at 00 for 30 min with in- electrically excitable neuroblastoma cells and compare these creasing concentrations (up to 150 mg original brain wet properties to those of the scorpion toxin receptor site described weight/ml) of the membrane fraction. These samples were then previously (10, 11). subjected to centrifugation for 5 min in a Beckman model B Microfuge and the [3H]saxitoxin remaining in the supernatant EXPERIMENTAL PROCEDURE was determined by scintillation assay and by measuring the The methods for growth of neuroblastoma cells (9), purification inhibition of the action potential Na+ ionophore as described and iodination of scorpion toxin (9, 11), measurement of Na+ (9). If the [3H]saxitoxin is pure, as suggested by the paper electrophoresis patterns, then the binding of 3H radioactivity The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked * Present address: Department of Pharmacology, University of "advertiement" in accordance with 18 U. S. C. §1734 solely to indicate Washington, Seattle, WA 98105. this fact. t Schwarz, W, Palade, P., and W. A. Catterall, unpublished data. 218 Downloaded by guest on September 26, 2021 Biochemistry: Catterall and Morrow Proc. Natl. Acad. Sci. USA 75 (1978) 219 and the saxitoxin biologic activity should be identical-In fact, as found previously by Ritchie et al. (4), a significant fraction of the 3H remains in the supernatant after 100% of the saxitoxin X /0 biologic activity is bound. This fraction ranged from 20 to 45% 6 ~~~~~~~~~~~~0 of the 3H in different purified fractions and must represent impurity in the [3H]saxitoxin preparations. This procedure provides a sensitive test of the purity of the labeled toxin. z -6 To verify that the 3H bound by the brain membranes in these 0 experiments represented [3H]saxitoxin, parallel experiments 0 were carried out in the presence of 10,uM tetrodotoxin to sat- `0 40 urate all saxitoxin receptor sites. Under these conditions, only 5% as much 3H was bound. Therefore, the bound 3H was almost 0 entirely [3H]saxitoxin. We conclude that our [3H]saxitoxin 20 - preparations have radiochemical purities ranging from 55 to 0 80%. Experiments with these different preparations gave quantitatively identical results, suggesting that the impurities 0D/ 0. 1 present had little influence on the binding measurements. At Saxcitoxin, nM (0) _ .,, I , , , ,~~,I~ ~ ~ ~, ~ , , least a portion of the impurity is [3H]H20 produced by back 10 100 1000 exchange from [3H]saxitoxin during electrophoresis and sub- 13H]Saxitoxin, ,sCilliter (a) sequent manipulations (4). Our initial attempts to remove the FIG. 1. Inhibition of the action potential Na+ ionophore by other impurities by thin-layer chromatography have not been [3Hjsaxitoxin and native saxitoxin. N18 cells were incubated with 100 successful. nM scorpion toxin for 30 min at 360 and then the initial rate of 22Na+ [3H]Saxitoxin Binding Assay. Saxitoxin binding was mea- influx was measured in the presence of 200 ,M veratridine and the sured in a medium consisting of 50 mM N-2-hydroxyethylpi- indicated concentrations of saxitoxin or [3H]saxitoxin as described perazine-N'-2-ethanesulfonic acid (adjusted to pH 7.4 with Tris (9). base), 130 mM choline chloride, 5.4 mM KC1, 0.8mM MgSO4, this is an incorrect assumption. Using their method (see Ex- and 5.5 mM glucose. At 36°, saxitoxin inhibition of the action perimental Procedure), we found that 55% of the 3H inthis potential Na+ ionophore of neuroblastoma cells is complete in preparation (Fig. 1) was associated with saxitoxin and therefore 10 min and binding of [3H]saxitoxin is complete in 10 min. In the specific radioactivity of the saxitoxin was 22.7 Ci/mmol. these experiments, cells in multiwell plates were incubated with Other preparations ranged up to 80% radiochemical purity with [3H]saxitoxin for 20 min at 36° to allow completion of the similar specific radioactivities. binding reaction. The inhibition of action potential Na+ iono- Binding of [3HJSaxitoxin to the Action Potential Na+ lo- phores in nerve axons and neuroblastoma cells by saxitoxin is nophore. Inhibition of the action potential Na+ ionophore of rapidly reversible. Bound [3H]saxitoxin dissociated from the neuroblastoma cells by saxitoxin is reversible and saturable and cells with a half-time of approximately 75 sec at 00. In the has an inhibition constant (KI) of 3.5 nM. Therefore, binding binding experiments, unbound [3H]saxitoxin was removed by experiments were designed to detect a saturable component of washing three times at 00 with 3 ml of wash medium consisting [3H]saxitoxin binding having a KD of approximately 3.5 nM. of 163 mM choline chloride, 5 mM N-2-hydroxyethylpipera- Fig.
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