Bookshelf

Box ANeurotoxins That Act on Postsynaptic Receptors

Poisonous plants and venomous animals are widespread in nature. The toxins they produce have been used for a variety of purposes, including hunting, healing, mind-altering, and, more recently, research. Many of these toxins have potent actions on the nervous system, often interfering with synaptic transmission by targeting neurotransmitter receptors. The poisons found in some organisms contain a single type of toxin, whereas others contain a mixture of tens or even hundreds of toxins.

Given the central role of ACh receptors in mediating muscle contraction at neuromuscular junctions in numerous species, it is not surprising that a large number of natural toxins interfere with transmission at this synapse. In fact, the classification of nicotinic and muscarinic ACh receptors is based on the sensitivity of these receptors to the toxic plant alkaloids nicotine and muscarine, which activate nicotinic and muscarinic ACh receptors, respectively. Nicotine is derived from the dried leaves of the tobacco plant Nicotinia tabacum, and muscarine is from the poisonous red mushroom Amanita muscaria. Both toxins are stimulants that produce nausea, vomiting, mental confusion, and convulsions. Muscarine poisoning can also lead to circulatory collapse, coma, and death.

The poison α-bungarotoxin, one of many peptides that together make up the venom of the banded krait, Bungarus multicinctus (figure A), blocks transmission at neuromuscular junctions and is used by the snake to paralyze its prey. This 74-amino-acid toxin blocks neuromuscular transmission by irreversibly binding to nicotinic ACh receptors, thus preventing ACh from opening postsynaptic ion channels. Paralysis ensues because skeletal muscles can no longer be activated by motor neurons. As a result of its specificity and its high affinity for nicotinic ACh receptors, α-bungarotoxin has contributed greatly to understanding the ACh receptor molecule. Other snake toxins that block nicotinic ACh receptors are cobra α-neurotoxin and the sea snake peptide erabutoxin. The same strategy used by these snakes to paralyze prey was adopted by South American Indians who used curare, a mixture of plant toxins from Chondodendron tomentosum, as an arrowhead poison to immobilize their quarry. Curare also blocks nicotinic ACh receptors; the active agent is the alkaloid δ-tubocurarine.

Another interesting class of animal toxins that selectively block nicotinic ACh and other receptors includes the peptides produced by fish-hunting marine cone snails (figure B). These colorful snails kill small fish by “shooting” venomous darts into them. The venom contains hundreds of peptides, known as the conotoxins, many of which target proteins that are important in synaptic transmission. There are conotoxin peptides that block Ca²⁺ channels, Na⁺ channels, glutamate receptors, and ACh receptors. The array of physiological responses produced by these peptides all serve to immobilize any prey unfortunate enough to encounter the cone snail. Many other organisms, including other mollusks, corals, worms, and frogs, also utilize toxins containing specific blockers of ACh receptors.

Other natural toxins have mind- or behavior-altering effects and in some cases have been used for thousands of years by shamans and, more recently, physicians. Two examples are plant alkaloid toxins that block muscarinic ACh receptors: atropine from deadly nightshade (belladonna), and scopolamine from henbane. Because these plants grow wild in many parts of the world, exposure is not unusual. Poisoning by either toxin can also lead to coma and death.

Another postsynaptic neurotoxin that, like nicotine, is used as a social drug is found in the seeds from the betel nut, Areca catechu (figure C). Betel nut chewing, although unknown in the United States, is practiced by up to 25% of the population in India, Bangladesh, Ceylon, Malaysia, and the Philippines. Chewing these nuts produces a euphoria caused by arecoline, an alkaloid agonist of nicotinic ACh receptors. Like nicotine, arecoline is an addictive central nervous system stimulant.

Many other neurotoxins alter transmission at noncholinergic synapses. For example, amino acids found in certain mushrooms, algae, and seeds are potent glutamate receptor agonists. The excitotoxic amino acids kainate, from the red alga Digenea simplex, and quisqualate, from the seed of Quisqualis indica, are used to separate two families of non-NMDA glutamate receptors (see text). Other neurotoxic amino acid activators of glutamate receptors include ibotenic acid and acromelic acid, both found in mushrooms, and domoate, which occurs in algae, seaweed, and mussels. Another large group of peptide neurotoxins blocks glutamate receptors. These include the α-agatoxins from the funnel web spider, NSTX-3 from the orb weaver spider, Joro toxin from the Joro spider, and β-philanthotoxin from wasp venom, as well as many cone snail toxins.

All the toxins discussed so far target excitatory synapses. The inhibitory GABA and glycine receptors, however, have not been overlooked by the exigencies of survival. Strychnine, an alkaloid extracted from the seeds of Strychnos nux-vomica, is the only drug known to have specific actions on transmission at glycinergic synapses. Because the toxin blocks glycine receptors, strychnine poisoning causes overactivity in the spinal cord and brainstem, leading to seizures. Strychnine is used commercially as a poison for rodents. Neurotoxins that block GABA_A receptors include plant alkaloids such as bicuculline from Dutchman's breeches and picrotoxin from Anamerta cocculus. Dieldrin, a commercial insecticide, also blocks these receptors. These agents are, like strychnine, powerful central nervous system stimulants. Muscimol, a mushroom toxin that is a powerful depressant as well as a hallucinogen, activates GABA_A receptors. A synthetic analogue of GABA, baclofen, is a GABA_B agonist that reduces EPSPs in some brainstem neurons and is used clinically to reduce the frequency and severity of muscle spasms.

Chemical warfare between species has thus given rise to a staggering array of molecules that target synapses throughout the nervous system. Although these toxins are designed to defeat normal synaptic transmission, they have also provided a set of powerful tools to understand postsynaptic mechanisms.

(A) The banded krait Bungarus multicinctus. (B) A marine cone snail (Conus sp.) uses venomous darts to kill a small fish. (C) Betel nuts, Areca catechu, growing in Malaysia. (A, Robert Zappalorti/Photo Researchers, Inc.; B, Zoya Maslak and Baldomera Olivera, University of Utah; C, Fletcher Baylis/Photo Researchers, Inc.)