Snake Venoms and the Neuromuscular Junction

Robert L. Lewis, M.D.; Ludwig Gutmann, M.D.

Disclosures

Semin Neurol. 2004;24(2) 

In This Article

Postsynaptic Inhibition

Postsynaptically active toxins are commonly called α-neurotoxins.[12] At present over 100 postsynaptic neurotoxins have been identified and sequenced.[9] All of the toxins are from the venoms of snakes of families Elapidae and Hydrophiidae.[14] There are often referred to as ''curare-mimetic toxins'' due to their similarity in action to the reversible acetylcholine receptor antagonist curare.[9] The postsynaptically, active toxins from a closely related homologous group possess several conservative residues and fold into a comparable three-loop structure.[6] They are subdivided into two main groups. The short-chain toxins (60 to 62 amino acids long) are arranged in a single chain and cross-linked by four disulphide bridges. The long-chain toxins (66 to 74 amino acids long) are also arranged in a single chain but are cross-linked by five disulphide bridges.[12] The acetylcholine receptor is the primary signal transducer at the neuromuscular junction and is a multisubunit, intrinsic membrane protein.[23] Both the short and the long toxins bind specifically to acetylcholine receptors, preventing the interaction between acetylcholine and receptors on postsynaptic membrane. This subsequently prevents the opening of the sodium channel associated with the acetylcholine receptor and results in neuromuscular blockade.[9] The binding of both acetylcholine and the α-neurotoxins involves a highly conserved domain of the acetylcholine receptor, the α-subunit.[24] The degree of inhibition is a function of receptor occupancy and receptor structure. In humans, some α-neurotoxins do not bind irreversibly and some do not bind at all. The human α-subunit of the acetylcholine receptor does not contain tryptophan in position 187, which is essential for the binding of the short-chain neurotoxin present in the venom of Enhydrina schistose.[14]

Most postsynaptically active toxins, such as a bungarotoxin from the banded krait, are reported to bind irreversibly to the acetylcholine receptor.[23] Clinicians, however, have reported that treatment with appropriate antivenom can result in rapid reversal of paralysis. It is suggested that antivenom accelerates the dissociation of the toxin-receptor complex, which leads to a reversal of paralysis.[12] Diagnostically, α-bungarotoxin and other α-neurotoxins are utilized for making quantitative studies on acetylcholine receptor density and turnover and for the assay of antibodies directed toward the acetylcholine receptor antibodies in patients with myasthenia gravis.[14,23]

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