Fasciculins are a class of toxic proteins found in certain snake venoms, notably some species of mamba. Investigations have revealed distinct forms in some green mamba venoms, in particular FAS1 and FAS2 [1] Fasciculins are so called because they cause intense fasciculation in muscle fascicles of susceptible organisms, such as the preferred prey of the snakes. This effect helps to incapacitate the muscles, either killing the prey, or paralysing it so that the snake can swallow it.
The mechanism of action of FAS proteins is associated with attachment to molecules within muscular acetylcholinesterase, and at neuromuscular junctions, thus conferring their ability to interfere with neuromodulatory inhibition. [2]
Fasciculins from mambas inhibit mammalian and fish acetylcholinesterases intensely, but are less active against the corresponding enzymes in insects, reptiles and birds. As one might expect of fast-acting venoms, they are fairly small proteins of about 61 amino acid residues. Their three-dimensional shape is three-fingered, and is secured by four cross-linking disulfide bridges.
Venom disrupters of acetylcholine neurotransmission generally penetrate the neuromuscular junction, where they interfere with either the production or reception of acetylcholine, or the hydrolysis of acetylcholine after it has achieved its function of neurotransmission; mamba fasciculins prevent the final stage of this process by binding to acetylcholinesterase and blocking its action on acetylcholine; the result is that after the acetylcholine has transmitted the required stimulus, it continues with the stimulus after it has become inappropriate. [2] That mechanism is in some ways similar to the effect of the so-called organophosphate nerve agents; the blockage of the acetylcholinesterase action is what causes the fasciculation that inspired the name fasciculin.
In mammalian acetylcholinesterase two conserved peripheral anionic residues form part of the enzyme where the FAS molecule docks. Insect and avian acetylcholinesterases lack the two residues in those positions, and that drastically reduces their affinity for mamba fasciculins. However, there is a significant, though reduced, toxic effect, because several basic residues in the venom protein still establish and maintain contacts with the enzyme. This is unusual in protein complementarity, in that it involves attractions between multiple charged residues, but without any salt linkage between the molecules. [3]
Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters:
A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.
Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is usually injected by unique fangs during a bite, though some species are also able to spit venom.
End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.
The black mamba is a species of highly venomous snake belonging to the family Elapidae. It is native to parts of sub-Saharan Africa. First formally described by Albert Günther in 1864, it is the second-longest venomous snake after the king cobra; mature specimens generally exceed 2 m and commonly grow to 3 m (9.8 ft). Specimens of 4.3 to 4.5 m have been reported. It varies in colour from grey to dark brown. Juvenile black mambas tend to be paler than adults and darken with age. Despite the common name, the black mamba is not black; the colour name describes rather the inside of its mouth, which it displays when feeling threatened.
Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.
α-Bungarotoxin is one of the bungarotoxins, components of the venom of the elapid Taiwanese banded krait snake. It is a type of α-neurotoxin, a neurotoxic protein that is known to bind competitively and in a relatively irreversible manner to the nicotinic acetylcholine receptor found at the neuromuscular junction, causing paralysis, respiratory failure, and death in the victim. It has also been shown to play an antagonistic role in the binding of the α7 nicotinic acetylcholine receptor in the brain, and as such has numerous applications in neuroscience research.
Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.
Bungarotoxins are toxins found in the venom of snakes and kraits. Bites from these animals can result in severe symptoms including bleeding or hemorrhage, paralysis and tissue damage that can result in amputation. The paralytic effects of venom are particularly dangerous as they can impair breathing. These symptoms are the result of bungarotoxin presence in the venom. In actuality, venom contains several distinct bungarotoxins, each varying in which receptors they act on and how powerful they are.
Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme that catalyzes the breakdown of acetylcholine and some other choline esters that function as neurotransmitters:
Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.
α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.
Mambalgins are peptides found in the venom of the black mamba, an elapid snake. Mambalgins are members of the three-finger toxin (3FTx) protein family and have the characteristic three-finger protein fold. First reported by French researchers in 2012, mambalgins are unusual members of the 3FTx family in that they have the in vivo effect of causing analgesia without apparent toxicity. Their mechanism of action is potent inhibition of acid-sensing ion channels.
Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).
Tetanic fade refers to the diminishing muscle twitch response from an evoked potential stimulation of muscle under the effect of either a non-depolarizing neuromuscular blocking agent, or a muscle that is under a phase 2 depolarizing neuromuscular blocking agent.
Crotoxin (CTX) is the main toxic compound in the snake venom of the South American rattlesnake, Crotalus durissus terrificus. Crotoxin is a heterodimeric beta-neurotoxin, composed of an acidic, non-toxic and non-enzymatic subunit (CA), and a basic, weakly toxic, phospholipase A2 protein (CB). This neurotoxin causes paralysis by both pre- and postsynaptic blocking of acetylcholine signalling.
Notexin is a toxin produced by the tiger snake (Notechis scutatus). It is a myotoxic and presynaptic, neurotoxic phospholipase A2 (PLA2s). These are enzymes that hydrolyze the bond between a fatty acid tail and glycerol in fatty acids on the 2-position.
Pseudonajatoxin b, or Pt-b, is a highly potent and lethal long-chain α-neurotoxin found in the venom of the eastern brown snake. While the pharmacodynamics of pseudonajatoxin b are currently undocumented, α-neurotoxins are known to cause neuromuscular paralysis by blocking cholinergic neurotransmission.