Nereistoxin: a naturally occurring toxin with redox effects on neuronal nicotinic acetylcholine receptors in chick retina.
Nereistoxin (NTX; 4-N,N-dimethylamino-1,2-dithiolane) is previously reported to block both muscle and neuronal nicotinic acetylcholine receptors, and reversibly inhibit radioligand binding to Torpedo nicotinic receptors. Here, we studied redox effects of NTX on neuronal nicotinic receptors in chick retinas by electrophysiological recordings and by [125I]neuronal bungarotoxin binding. NTX blocked retinal responses to the nicotinic agonist dimethylphenylpiperazinium (300 microM, 2 sec) with an IC50 of 3.5 microM. NTX inhibition was selective for nicotinic receptors, long lasting and not reversible upon washing. The nonselective oxidizing compound dithiobis(nitrobenzoic acid) (1 mM) transiently and repetitively reversed NTX (100 microM) inhibition (85% recovery). After application of the alkylating agent bromoacetylcholine (2 or 100 microM, with 2 microM neostigmine), dithiobis(nitrobenzoic acid) could no longer restore nicotinic function. d-Tubocurarine (300 microM) equally protected against alkylation with bromoacetylcholine (2 microM) after dithiothreitol (2 mM) or NTX treatment. The action of NTX differs from that of dithiothreitol because the agonist dimethylphenylpiperazinium (30 microM) protects against inactivation by dithiothreitol, but not by NTX. NTX reversibly inhibited [125I]neuronal bungarotoxin binding to chick retinal homogenates (IC50 = 16 microM). The present study suggests that nereistoxin or a metabolite is a potent antagonist as well as a selective reducing agent for nicotinic receptors in chick retina. As a dithiolane, this latter action by nereistoxin remains to be explained.
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Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Northeastern University, Boston, Massachusetts.
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D000109:Acetylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000378:metabolism; D002645:Chickens; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004228:Dithionitrobenzoic Acid / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D008387:Marine Toxins / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012160:Retina / Q000187:drug effects*; D014403:Tubocurarine / Q000494:pharmacology
D002038:Bungarotoxins; D008387:Marine Toxins; D011978:Receptors, Nicotinic; C025633:nereistoxin; D004246:Dimethylphenylpiperazinium Iodide; D004228:Dithionitrobenzoic Acid; D000109:Acetylcholine; D004229:Dithiothreitol; D014403:Tubocurarine