Neuromuscular effects of candoxin, a novel toxin from the venom of the Malayan krait (Bungarus candidus).
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 alpha-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 alpha-neurotoxins that produce little or no fade. 4 Electrophysiological experiments confirmed that candoxin produced a readily reversible blockade (IC(50) approximately 10 nM) of oocyte-expressed muscle (alphabetagammadelta) nAChRs. Like alpha-conotoxin MI, well known for its preferential binding to the alpha/delta interface of the muscle (alphabetagammadelta) nAChR, candoxin also demonstrated a biphasic concentration-response inhibition curve with a high- (IC(50) approximately 2.2 nM) and a low- (IC(50) approximately 98 nM) affinity component, suggesting that it may exhibit differential affinities for the two binding sites on the muscle (alphabetagammadelta) receptor. In contrast, curaremimetic alpha-neurotoxins have been reported to antagonize both binding sites with equal affinity.
Nirthanan
S
S
Venom and Toxin Research Programme, Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore.
Charpantier
E
E
Gopalakrishnakone
P
P
Gwee
M C E
MC
Khoo
H E
HE
Cheah
L S
LS
Kini
R M
RM
Bertrand
D
D
D000595:Amino Acid Sequence; D000818:Animals; D017838:Bungarus / Q000378:metabolism*; D002478:Cells, Cultured; D002645:Chickens; D003603:Cytotoxins / Q000737:chemistry* / Q000493:pharmacokinetics*; D003964:Diaphragm / Q000187:drug effects / Q000294:innervation; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006168:Guinea Pigs; D008296:Malaysia; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D019148:Neuromuscular Blockade; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000737:chemistry / Q000493:pharmacokinetics*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010791:Phrenic Nerve / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects; D012910:Snake Venoms
D003603:Cytotoxins; D009498:Neurotoxins; D011978:Receptors, Nicotinic; D012910:Snake Venoms; C459604:candoxin