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Histrionicotoxin Enhances Agonist-Induced Desensitization of Acetylcholine Receptor

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Histrionicotoxin Enhances Agonist-Induced Desensitization of Acetylcholine Receptor Proc. Nati. Acad. Sci. USA Vol. 74, No. 12, pp. 5754-5758, December 1977 Neurobiology Histrionicotoxin enhances agonist-induced desensitization of acetylcholine receptor (22Na+ uptake/'251-labeled a-bungarotoxin binding) WOLFGANG BURGERMEISTER*, WILLIAM A. CATTERALLtt, AND BERNHARD WITKOP* * Laboratory of Chemistry, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland, 20014; and t Laboratory of Biochemical Genetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, NMaryland, 20014 Contributed by Bernhard Witkop September 6, 1977 ABSTRACT Dihydroisohistrionicotoxin inhibits acetyl- of Health, who isolated it from the skin of Dendrobates his- choline receptor-dependent 22Na+ uptake of cultured chick trionicus (1). a-Bungarotoxin was purified from Iyophilized muscle cells with a KI of 0.2 1AM. The inhibition is noncompet- itive with respect to agonists. The toxin enhances desensitization venom of Bungarus multicinctus (Miami Serpentarium) and of the receptor by agonists which is accompanied by a 10-fold radio-iodinated as described by Vogel et al. (9). Chemicals were increase in receptor affinity for agonists. Dihydroisohistrioni- obtained from the following sources: carbamylcholine chloride, cotoxin increases the affinity of the desensitized form of the acetylcholine chloride, d-tubocurarine chloride, ouabain, and receptor for agonists but not antagonists. The results suggest that D-arabinofuranosylcytosine from Sigma; decamethonium dihydroisohistrionicotoxin inhibits the acetylcholine receptor bromide and gallamine triethiodide from K & K Laboratories; by causing an increase in the affinity of the desensitized form of the receptor for agonists and thereby stabilizing the de- nicotine dihydrochloride from Baker; F3H]leucine from New sensitized state. England Nuclear; and calf skin collagen from Calbiochem. Chick embryo extract was prepared as described in ref. 10. The pharmacological properties of histrionicotoxins (HTX), Other chemicals used for tissue culture were obtained from the alkaloids isolated from skin extracts of the tropical South same sources as described in ref. 8. American frog, Dendrobates histrionicus (1), have been studied Muscle Culture. Suspensions of single muscle cells from thigh by using electrophysiological and biochemical approaches. In muscle of 11-day-old chick embryos were prepared essentially mammalian and amphibian nerve-muscle preparations, HTX, as described by Fischbach (11). Cells were seeded at a density as well as its analogs dihydroisohistrionicotoxin (H2-HTX) and of 40,000/cm2 in collagen-coated multiwells (Costar 1.6 cm dodecahydrohistrionicotoxin (H12-HTX), act as reversible diameter) and grown as described (8). Cultures were used after blockers of neuromuscular transmission (2-4). They also block 6-9 days in vitro. Two days before use the cultures were treated noncompetitively the depolarization produced by carbamyl- with feeding medium supplemented with 10 pM D-arabino choline on the isolated electroplax of Electrophorus electricus furanosylcytosine to reduce the fibroblast population (11) and (3, 5). Binding of [3Mlacetylcholine (5) and a-i3Hlbungarotoxin with 0.2 ACi of [l3Hlleucine per ml to allow use of 3H cpm as a (6) to the nicotinic acetylcholine receptor is inhibited by HTX measure of protein recovery in experiments. and its analogs only at concentrations 10-fold greater than those Measurement of 22Na+ Uptake. Rates of uptake of 22Na+ required for inhibition of depolarization. At concentrations that into cells in monolayer cultures were measured at 360 as de- inhibit depolarization, HTX causes a small enhancement of the scribed (8, 12). The cultures were preincubated at 36° with binding of 13Hjacetylcholine (5). Binding studies with [f131- buffer 1 150 mM N-2-hydroxyethylpiperazine-N'-2-ethane- H12-HTX revealed that the toxin binds with a high affinity to sulfonic acid (Hepes)/13 mM NaCl/122 mM KCI/1.8 mM a protein fraction from Torpedo ocellata electric organ that CaC12/0.8 mM MgSO4/5.5 mM glucose, adjusted to pH 7.4 could be separated from the acetylcholine binding protein (7). with Tris] containing the effectors noted in the figure legends From the results mentioned so far it was postulated that HTX and 5 mM ouabain for inhibition of the active extrusion of Na+ acts by binding to the ion conductance modulator associated catalyzed by Na+- and K+-activated ATPase. These conditions with the acetylcholine receptor (2, 4, 7) or as an allosteric ligand for preincubation were chosen so that the ionic composition of of the acetylcholine receptor itself (3, 5). the external medium was identical to that inside the cells. Under As shown by Catterall (8), cultured embryonic chick muscle these conditions, preincubation with agonists causes no change cells provide a suitable system for studying ligand binding as in the ionic concentration gradients or the membrane poten- well as Na+ transport activity of the nicotinic acetylcholine tial. receptor. The receptor-dependent 22Na+ uptake of the cells is Uptake was initiated by incubating the cultures with buffer desensitized during exposure to carbamylcholine (8). In the 2 (50 mM Hepes/130 mM NaCl/5.4 mM KCl/1.8 mM present investigation we have used cultured muscle cells to CaC12/0.8 mM MgSO4/5.5 mM glucose/1.0 mM NaH2PO4, study effects of H2-HTX on the activation and desensitization adjusted to pH 7.4 with NaOH) containing 5 yCi of 22NaCl per of the acetylcholine receptor and on the binding of cholinergic ml, 0, 1, or 10 mM carbamylcholine, 5 mM ouabain, and the ligands to the receptor. effectors noted in the figure legends. After 30 sec at 360, uptake was terminated by removing the radioactive uptake buffer and MATERIALS AND METHODS Dihydroisohistrionicotoxin was kindly provided by John W. Abbreviations: HTX, histrionicotoxin; H2-HTX, dihydroisohistrioni- Daly, Laboratory of Chemistry, NIAMDD, National Institutes cotoxin; H12-HTX, dodecahydrohistrionicotoxin; Hepes, N-2-hy- droxyethylpiperazine-N'-2-ethanesulfonic acid; buffer 1, 50 mM The costs of publication of this article were defrayed in part by the Hepes/13 mM NaCI/122 mM KCl/1.8 mM CaCl2/0.8 mM MgSO4/ payment of page charges. This article must therefore be hereby marked 5.5 mM glucose, adjusted to pH 7.4 with Tris. "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate f Present address: Department of Pharmacology, School of Medicine, this fact. University of Washington, Seattle, WA 98105 5754 Neurobiology: Burgermeister et al. Proc. Natl. Acad. Sci. USA 74 (1977) 5755 EE 200 0 o A C150- E a loo 50- - Log molrity carhamylcholine Fl(;. 2. Desensitization of receptor-dependent Na+ transport 9 8 7 6 5 activity by carbamylcholine in the absence and presence of H2-HTX. ---Log molarity H2-HTX Muscle cells were preincubated for 30 min with the indicated con- Fi(u. 1. Inhibition of receptor-dependent Na+ transport by centrations of carbamylcholine (0), carbamvlcholine plus 0.05 pM H2,-HTX. Muscle cells were preincubated for 30 min with the indi- H,-HTX (A), or carbamylcholine plus 0.1 pM H9-HTX (0). 22Na+ cated concentrations of H ,-HTX. 22Na+ uptake was then measuired uptake was then measured for S30 sec in the presence of 1 mM car- for 30 sec in the presence of 1 mM (0) or 10 mM ( A) carbamylcholine bamylcholi ne. and the indicated concentrations of H9,-HTX. This indicates that H2-HTX is a noncompetitive inhibitor of the receptor stimulation by carbamvlcholine. by washing three times at 360 with buffer 3 (164 mM NaCI/5.4 As was shown by Catterall (8), the receptor-dependent Na+ mM KCI/1.8 mM CaCJ2/0.8 mM MgSO4/5.0 Hepes, adjusted when the cultures mM transport activity desensitizes rapidly are to pH 7.4 with NaOH) containing 1 d-tubocurarine to exposed to carbamylcholine. Fig. 2 shows how the degree of inhibit receptor-activated ion movements. Cell monolayers desensitization depends on the concentration of carbamyl- were then suspended in 0.4 M NaOH and radioactivity was of 30 in scintillation counter. rates in nmol of choline that is present during a preincubation period min. measured a Uptake Half-maximal desensitization is caused by 40 MiM carbamyl- 22Na/min per mg of cell protein were calculated from the choline. By contrast, half-maximal activation of receptor- measurements of 22Na+ taken up and determinations of cell dependent Na+ transport requires approximately 400 jM protein by a modification of the method of Lowry et al. (13). carbamylcholine both under these experimental conditions and Values were corrected for variable protein recovery during the those described previously (8). Therefore, the apparent affinity assay and washing procedures on the basis of the [3H]leucine for desensitization of the receptor by carbamylcholine is 10-fold radioactivity recovered in each sample. Carbamylcholine- greater than the apparent affinity for activation of the receptor dependent 22Na+ uptake was determined as the difference of of by carbamylcholine. uptake measured in the presence and absence carbamyl- In the presence of 0.05 pMNi and 0.1 jIM H2-HTX, half-max- choline, and has been plotted in the figures. imal desensitization was observed at 14 pM and 10 pM car- Binding of 1125IJMono- and [1251J-Diiodo-a-bungarotoxin. bamylcholine, respectively (Fig. 2). Thus, H2-HTX enhances Binding experiments were carried out at 36° as described (8), the carbamylcholine-induced desensitization and causes a shift with buffer 1 supplemented with 1 mg of bovine serum albu- of the desensitization against concentration profile to lower min per ml. Excess toxin was eluted with three (if 3 nM bun- concentrations. When the cells were preincubated for 30 min garotoxin was used) or five (if >3 nM bungarotoxin was used) with 20 ,M carbamvlcholine plus increasing concentrations of I-min washes at 360 with buffer 4 (163 mM choline chloride/ H2-HTX and then assayed in the presence of H2-HTX, the in- 1.8 mM CaCI2/0.8 mM MgSO4/5 mM Hepes, adjusted to pH hibition in comparison to the H.2-HTX concentration profile 7.4 with Tris).
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