Neuromuscular effects of candoxin, a novel toxin from the venom of the Malayan krait (Bungarus candidus).
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1 Candoxin (MW 7334.6), a novel toxin isolated from the venom of the Malayan krait Bungarus candidus, belongs to the poorly characterized subfamily of nonconventional three-finger toxins present in Elapid venoms. The current study details the pharmacological effects of candoxin at the neuromuscular junction. 2 Candoxin produces a novel pattern of neuromuscular blockade in isolated nerve-muscle preparations and the tibialis anterior muscle of anaesthetized rats. In contrast to the virtually irreversible postsynaptic neuromuscular blockade produced by curaremimetic a-neurotoxins, the neuromuscular blockade produced by candoxin was rapidly and completely reversed by washing or by the addition of the anticholinesterase neostigmine. 3 Candoxin also produced significant train-of-four fade during the onset of and recovery from neuromuscular blockade, both, in vitro and in vivo. The fade phenomenon has been attributed to a blockade of putative presynaptic nicotinic acetylcholine receptors (nAChRs) that mediate a positive feedback mechanism and maintain adequate transmitter release during rapid repetitive stimulation. In this respect, candoxin closely resembles the neuromuscular blocking effects of d-tubocurarine, and differs markedly from curaremimetic a-neurotoxins that produce little or no fade. 4 Electrophysiological experiments confirmed that candoxin produced a readily reversible blockade (IC50~10 nM) of oocyte-expressed muscle (a߿d) nAChRs. Like a-conotoxin MI, well known for its preferential binding to the a/d interface of the muscle (a߿d) nAChR, candoxin also demonstrated a biphasic concentration - response inhibition curve with a high- (IC50~2.2 nM) and a low-(IC50~98 nM) affinity component, suggesting that it may exhibit differential affinities for the two binding sites on the muscle (a߿d) receptor. In contrast, curaremimetic a-neurotoxins have been reported to antagonize both binding sites with equal affinity.
British Journal of Pharmacology