Candoxin, a novel toxin from Bungarus candidus, is a reversible antagonist of muscle (alphabetagammadelta ) but a poorly reversible antagonist of neuronal alpha 7 nicotinic acetylcholine receptors.
In contrast to most short and long chain curaremimetic neurotoxins that produce virtually irreversible neuromuscular blockade in isolated nerve-muscle preparations, candoxin, a novel three-finger toxin from the Malayan krait Bungarus candidus, produced postjunctional neuromuscular blockade that was readily and completely reversible. Nanomolar concentrations of candoxin (IC(50) = approximately 10 nm) also blocked acetylcholine-evoked currents in oocyte-expressed rat muscle (alphabetagammadelta) nicotinic acetylcholine receptors in a reversible manner. In contrast, it produced a poorly reversible block (IC(50) = approximately 50 nm) of rat neuronal alpha7 receptors, clearly showing diverse functional profiles for the two nicotinic receptor subsets. Interestingly, candoxin lacks the helix-like segment cyclized by the fifth disulfide bridge at the tip of the middle loop of long chain neurotoxins, reported to be critical for binding to alpha7 receptors. However, its solution NMR structure showed the presence of some functionally invariant residues involved in the interaction of both short and long chain neurotoxins to muscle (alphabetagammadelta) and long chain neurotoxins to alpha7 receptors. Candoxin is therefore a novel toxin that shares a common scaffold with long chain alpha-neurotoxins but possibly utilizes additional functional determinants that assist in recognizing neuronal alpha7 receptors.
Nirthanan
Selvanayagam
S
Venom and Toxin Research Programme, Faculty of Medicine, National University of Singapore, Singapore 119260, Republic of Singapore.
Charpantier
Eric
E
Gopalakrishnakone
Ponnampalam
P
Gwee
Matthew C E
MC
Khoo
Hoon-Eng
HE
Cheah
Li-Sam
LS
Bertrand
Daniel
D
Kini
R Manjunatha
RM
D000109:Acetylcholine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D017838:Bungarus; D002851:Chromatography, High Pressure Liquid; D003603:Cytotoxins / Q000302:isolation & purification / Q000494:pharmacology*; D004594:Electrophysiology; D019054:Evoked Potentials, Motor / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012910:Snake Venoms; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D003603:Cytotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D012910:Snake Venoms; C459604:candoxin; D000109:Acetylcholine