Receptor Inhibitors: Bungarotoxin and Curare

Inhibitors of the Nicotinic Acetylcholine Receptor (nAChR)

• Bungarotoxin (Bgtx)

Bgtx is a group of closely related neurotoxic proteins of the three-finger toxin superfamily, which was found in the venom of kraits, including Bungarus multicinctus. These toxins may be classified into four types according to their pharmacological activity, including α, β, γ, κ. α-Bgtx is a small protein isolated from the venom of Bungarus multicinctus, which inhibits the action of acetylcholine on muscle in a practically irreversible manner, alternatively, the toxin might interfere with the access of acetylcholine to the receptors. β-Bgtx is a basic protein consisting of two dissimilar polypeptide subunits, which acts presynaptically causing excessive acetylcholine release and subsequent depletion.

Fig.1 α-Bgtx and the structure of mouse nAChR α-subunit ECD in complex with α-Bgtx. (Lu, 2020)

• Curare

Curare is a common name for various plant extract alkaloid arrow poisons originating from indigenous peoples in Central and South America. Used as a paralyzing agent for hunting and therapeutic purposes. These poisons function by competitively and reversibly inhibiting the nAChRs, which is a subtype of acetylcholine receptor found at the neuromuscular junction. Historically, curare has been used as an effective treatment for tetanus or strychnine poisoning and as a paralyzing agent for surgical procedures.

Mechanism of Receptor Inhibitors

nAChRs contain two binding sites for snake venom neurotoxins. Either α-Bgtx or curare binds as a competitive antagonist to nAChRs, inhibiting ion flow and leading to paralysis.

Application in Scientific Discovery and Medicine

• Almost all vital biological processes can be disrupted by snake toxins, which either destroying muscle tissue or disrupting the function of the neuromuscular junction. Modern anesthetists can use a variety of muscle relaxants in anesthesia. The ability to produce muscle relaxation irrespective of sedation has permitted anesthetists to perform surgery smoothly.
• α-Bgtx plays an important role in determining many of the structural details of nAChRs. It can be conjugated to a fluorophore or enzyme for immunohistochemical staining of fixed tissues and visualization via light or fluorescence microscopy. α-Bgtx is a widely recognized tool for studying the transport, expression, and inhibition of nAChRs in the nervous system. By binding α-Bgtx, its imaging applications have been extended to other receptors, such as GABAARs.
• Curare/curare-derivatives are widely used paralytic agents in medical and surgical procedures. Recently, curare has been used in humans and animals to reduce and block shivering, diagnose myasthenia gravis, and manipulate neurosysnaptic transmission.

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Reference

1. Lu, Y.Z.; Kinetics of mouse and human muscle type nicotinic receptor channels. 2020.