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Modulation of Acetylcholine Release at Mouse Neuromuscular Junctions by Interaction of Three Homologous Scorpion Toxins with K+ Channels 1H

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Modulation of Acetylcholine Release at Mouse Neuromuscular Junctions by Interaction of Three Homologous Scorpion Toxins with K+ Channels 1H Brftish Joumal of Pharmacology (1995) 13A 1502-1506 B 1995 Stockton Press All rights reserved 0007-1188/95 $9.00 S Modulation of acetylcholine release at mouse neuromuscular junctions by interaction of three homologous scorpion toxins with K+ channels 1H. Vatanpour & 2A.L. Harvey Department of Physiology and Pharmacology, University of Strathclyde, Glasgow GI IXW 1 The effects of three scorpion toxins, charybdotoxin (CTX), iberiotoxin (IbTX), and noxiustoxin (NTX) have been studied on acetylcholine release and on K+ channels by means of twitch tension and electrophysiological recording techniques using isolated skeletal muscle preparations and by a radio- ligand binding assay using 1251I-labelled dendrotoxin I (DpI) and rat brain synaptosomal memb- ranes. 2 On chick biventer cervicis preparations, CTX and IbTX (125 nM) augmented the twitch responses to indirect muscle stimulation. Further, the increase (about 70-80% of control twitch height) was fast in onset, reaching a maximum within 25-30 min. NTX at 125 nm produced a slower augmentation of the twitch responses to indirect muscle stimulation, with the maximum response being seen after 40- 50 min. 3 On mouse triangularis sterni preparations, CTX (300 nM after 35-40 min) and IbTX (100 nM after 15 min) increased quantal content of the evoked endplate potentials (e.p.p.) by about two fold. However, NTX (300 nM) caused only a small increase in e.p.p. amplitude, which was followed by repetitive e.p.ps in response to single shock nerve stimulation after 40-50 min. 4 Extracellular recording of nerve terminal current waveforms in triangularis sterni preparations revealed that CTX and IbTX (3-100nM), but not NTX (100nM), blocked the Ca2"-activated K+ current, IK-Ca. However, there was no major change in the portion of the nerve terminal waveform associated with voltage-dependent K+ currents, IKV, 5 In the radioligand binding assay, NTX potently displaced labelled ['25I]-DpI, whereas CTX produced only partial displacement. However, IbTX did not displace ['25I]-DpI from its binding sites on rat brain synaptosomal membranes. 6 We conclude that these three structurally homologous scorpion toxins act on different K+ channels and that this leads to different patterns of facilitation of acetylcholine release. IbTX acts selectively on high conductance Ca2+-activated K+ channels, leading to an increase in the amplitude of e.p.ps without any other changes. NTX acts on voltage-dependent K+ channels that are sensitive to dendrotoxin and causes repetitive e.p.ps. CTX shares amino acid residues that exist in the structures of IbTX and NTX; CTX acts on both Ca2+- and voltage-dependent K+ channels. Keywords: Neurotoxins; potassium channels; neuromuscular junction; acetylcholine release; dendrotoxin; charybdotoxin; iberiotoxin; noxiustoxin Introduction Potassium channels with distinctive properties and phar- increase in transmitter release from cholinergic nerve ter- macological sensitivites play critical physiological roles in minals. many types of cells. Although several different genes Noxiustoxin (NTX), a 39-residue-chain peptide toxin from encoding K+ channel proteins have been cloned and ex- the scorpion Centruroides noxius, is known to block neuronal pressed in oocytes, it is still unclear which gene products are K+ channels (Carbone et al., 1987). It facilitated acetyl- important in regulation of such processes as neurotransmitter choline release in chick biventer cervicis preparations and release. One approach to the study of channel function in situ displayed binding of a radiolabelled dendrotoxin from synap- is to examine the effects of highly selective channel blockers. tosomal membranes from rat brain (Harvey et al., 1992). Polypeptide toxins from several Old World scorpions block NTX probably blocks dendrotoxin-sensitive voltage- voltage-gated inactivating K+ channels (for review, see dependent K+ channels in rat brain synaptosomal mem- Harvey et al., 1993). Moreover, some toxins from Leiurus branes (Harvey et al., 1992) and at higher concentrations it quinquestriatus hebraeus (e.g. charybdotoxin, CTX) block also blocks Ca2"-activated K+ channels from T-tubules of high-conductance Ca2"-activated K+ channels (Miller et al., skeletal muscle (NTX's Kd = 450 nM) (Valdivia et al., 1985) as well as voltage-gated inactivating K+ channels 1988). (Schneider et al., 1989; Schweitz et al., 1989; Blaustein et al., Iberiotoxin (IbTX) from Buthus tamulus venom consists of 1991). In contrast, venoms from several New World scor- a single polypeptide chain (37 residues) that can block IK-Ca pions contain polypeptides that selectively block only selectively; it does not block other types of K+ channels voltage-gated, non-inactivating K+ channels (Blaustein et al., (Galvez et al., 1990). IbTX displays 68% sequence identity 1991). The present paper describes the interactions of three with charybdotoxin (CTX). However, IbTX possesses four homologous scorpion toxins with K+ channels that lead to more acidic and one less basic amino acid residue than does CTX, making this toxin much less positively charged than the other peptide (Galvez et al., 1990). IbTX interacts with 1 Present address: Department of Pharmacology and Toxicology, CTX at a distinct site on the channel and modulates CTX Shaheed Beheshti University of Medical Sciences, Tehran, Iran. binding by an allosteric mechanism (Galvez et al., 1990; 2Author for correspondence. Candia et al., 1992). IbTx has recently been reported to 1503 H. Vatanpour & A.L. Harvey- ScorpionScorpio toxins andr transmitter release 1503 increase acetylcholine release at frog neuromuscular junctions period. The same recording site was used throughout each (Robitaille et al., 1993). experiment. CTX is a 37-amino acid peptide from the venom of the For extracellular recording, presynaptic waveforms were scorpion Leiurus quinquestriatus hebraeus, which was recorded with a glass microelectrode (2 M NaCl, 16-30 originally described as a potent blocker of high-conductance Megohms) placed inside the perineural sheath (near endplate Ca2+-activated K+ channels (Miller et al., 1985). Subse- areas) of one of the branches of an intercostal nerve (Mallart, quently, it was shown that CTX can also block the inac- 1985; Penner & Dreyer, 1986; Anderson et al., 1988). Usually tivating voltage-dependent K+ channel that is present in rat 50-70 waveforms were recorded at each time period. Pre- brain and human T lymphocytes, but not other types of K+ parations were stimulated at 0.5 Hz. Recording sites were channels (Gimenez-Gallego et al., 1988; Stuhmer et al., 1989; rejected if signal amplitude varied by more than 10% during Price et al., 1989; Oliva et al., 1991). CTx also binds to the first 15 min prior to addition of the test substance. dendrotoxin-sensitive proteins from brain membranes, imply- Physiological salt solution (10-20ml) containing toxins was ing an action on voltage-dependent K+ channels (Schweitz et aerated and recirculated through the tissue bath during al., 1989; Harvey et al., 1989). CTx has been found to electrophysiological recording. increase acetylcholine release at frog neuromuscular junctions (Robitaille & Charlton, 1992), although an earlier study on a Radioligand binding assay mouse preparation reported no effect under normal recording conditions (Anderson et al., 1988). Synaptosomal membranes were prepared from the brains of Neuronal membranes contain several distinct K+ conduc- 200-250 g male Sprague-Dawley rats (Harvey et al., 1989). tances that can be distinguished by their voltage-dependency Each brain was homogenized in 10 ml homogenization buffer and interactions with blocking agents (Rogawski, 1985). (32 mM sucrose, 2 mM Tris.HCl; pH 7.4) at 4C. The suspen- Potassium channels contribute to the repolarization of the sion was centrifuged at 29000 r.p.m. for 10 min. The resulting membrane after an action potential and to the regulation of pellet was lysed by addition of 10 ml lysis buffer (5TnM the excitability of neurones, and they help to regulate the Tris.HCl; pH 8.1). The suspension was centrifuged at release of transmitter from nerve terminals. Their blocking by 20000 r.p.m. for a further 20 min, and the pellet was finally a K+ channel blocker (e.g., 3,4-diaminopyridine) can cause resuspended in 25 ml synaptosomal buffer of the following prolongation of the time course of depolarization and inc- composition (mM): NaCl 130, KCl 3, CaCl2 2, MgCl2 2, and rease transmitter release. The importance of particular sub- Tris.HCl 20, pH 7.4 Aliquots (5 x 5 ml) were stored frozen types of K+ channel to nerve terminal function cannot be until needed. For competition binding experiments, 200 iLl of examined by use of agents such as 3,4-diaminopyridine or membrane suspension was incubated at room temperature tetraethylammonium because of their low selectivity. It was (19-21°C) with a standard amount (1-3 nM) of '25I-toxin I hoped that a comparison of effects of the more selective and various amounts of competing toxin. The final volume blocking agents IbTx, CTX and NTX would reveal the was 0.5 ml. The membranes were collected by centrifugation physiological contributions of voltage- and Ca2"-dependent on a microfuge and radioactivity determined. K+ channels at motor nerve terminals in mouse skeletal muscle. Source of toxins NTX was isolated as described previously (Possani et al., 1982). CTX and IbTX were synthesized by Dr C. Vita Methods (DIEP, CEA Saclay, Gif sur Yvette, France). ['251]-DpI was prepared by F.A. De-Allie and Dr P.N. Strong (Neuromus- Hammersmith Hospital, London). Twitch tension recording cular Research Unit, Biventer cervicis nerve-muscle preparations (Ginsborg & Warriner, 1960) were isolated from 3-14 day old chicks and Results mounted with a resting tension of 0.5-1 g in 2 or 10 ml tissue baths containing physiological salt solution of the fol- Twitch tension experiments lowing composition (mM): NaCl 118.5, KCI 4.7, MgSO4 1.2, 11.1. The solu- CTX, IbTX and NTX were tested on indirectly stimulated KH2PO2 1.2, CaCl2 2.5, NaHCO3 25, glucose induced a was maintained at 33°C and was bubbled with 95% 02 chick biventer cervicis preparations.
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