Excitatory Neurotoxin: α-Latrotoxin

Introduction to α-Latrotoxin

Black widow spider α-latrotoxin, a member of the GTP-binding protein-coupled receptors (GPCRs) family, is a large protein with a size of about 120kDa. In general, α-latrotoxin consists of an N-terminal signal peptide (SP) domain, a conserved cysteine residues domain, a 22 ankyrin repeats domain, as well as a C-terminal domain. Among them, this conserved cysteine residues domain also contains two hydrophobic sequences that distribute across the cell membrane and fold in the nucleus of the α-latrotoxin. Nowadays, α-latrotoxin has been regarded as a powerful tool for revealing the mechanism of synaptic transmission in neurosciences. α-Latrotoxin can bind to its receptors on the presynaptic nerve terminals to further trigger the release of neurotransmitters by stimulating synaptic vesicle exocytosis.

Fig.1 Schematics of latrotoxin structure, its receptors, and action mechanisms at the presynaptic terminal. (Ovsepian, 2019)

Mechanism of Action of α-Latrotoxin

In the past few years of studies, the key role of α-latrotoxin in mediating the release of neurotransmitters and hormones have been confirmed in various types of cells, such as neuromuscular junctions, PC12 cell, pancreatic β-cells, neurohypophysis cells, and hormone-secreting cells. Moreover, pilot studies have suggested that high toxin concentration (>10 nM) of α-latrotoxin mainly induces the release of neurotransmitters by controlling the different functions of presynaptic structural elements. Another important ability of α-latrotoxin is to regulate Ca²⁺-independent neurotransmitter release. For instance, in the presence of calcium, α-latrotoxin inhibits the release of acetylcholine at the neuromuscular junction, and this inhibition disappears when calcium is removed. Numerous data have indicated that calcium controls the function of α-latrotoxin by regulating endocytosis in the nerves.

Receptors for α-Latrotoxin

Commonly, α-latrotoxin requires bind to specific receptors for stimulating neurosecretion in humans. Up to now, two groups of α-latrotoxin receptors, including Ca²⁺ dependent and Ca²⁺ independent receptors, have been purified and identified in the active zone of the presynaptic plasma membrane. Neurexins have been treated as typical Ca²⁺-dependent receptors that can bind to α-latrotoxin with high affinity. Also, CIRL/latrophilin has been considered as Ca²⁺-independent receptors for α-latrotoxin. Recent reports have shown that α-latrotoxin can bind with the intracellular G-protein signal region of CIRL/latrophilin for triggering the activation of exocytosis in vivo.

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Reference

1. Ovsepian, S. V.; et al. Neurobiology and therapeutic applications of neurotoxins targeting transmitter release. Pharmacology & therapeutics. 2019, 93: 135-155.