ABSTRACT
Natural neurotoxins have been succesfully used as tools to dissect the molecular mechanisms of synaptic transmission. Presynaptic calcium channels were detected and studied with conotoxins and agatoxins, the neurotoxins that are their specific and potent blockers. As another example, nerve terminal proteins synaptobrevin, syntaxin and SNAP-25 were identified as key components of the presynaptic docking-fusion machinery because they are proteolytically cleaved and thus disabled by tetanus and botulinum neurotoxins, well known inhibitors of neurosecretion. This chapter is devoted to yet another presynaptic neurotoxin α-latrotoxin which, in contrast to the bacterial toxins, is a strong and universal stimulator of neurotransmitter release. α-Latrotoxin is a large protein contained in Black Widow Spider venom. It acts by
stimulating intense exocytosis of synaptic vesicles in the nerve terminal and thus has been an invaluable tool in formulating the vesicular hypothesis of neurotransmitter release. Although the mechanism of action of α-latrotoxin is not completely understood, ample experimental data suggest an important role of neuronal membrane proteins which tightly bind α-latrotoxin molecules extracellularly and in some not yet clear manner participate in the activation of exocytosis by the toxin. These high-affinity α-latrotoxin-binding proteins are usually referred to as α-latrotoxin receptors. Due to the unique specificity and potency of α-latrotoxin, its receptors are generally considered as nerve terminal markers and significant components or regulators of exocytosis. α-Latrotoxin receptors were originally discovered in ligand-binding studies. They were
further characterized biochemically, purified and reconstituted in artificial lipid membranes. Recently, genes encoding these proteins were cloned and the valuable information about their structure became available. In this chapter, on the basis of
biochemical and structural data, we will discuss how α-latrotoxin receptors are involved in the effects of α-latrotoxin and what their physiological function might be. Several important yet controversial issues will be considered in view of the very recent data:
(1) How many types of α-latrotoxin receptor exist and how are they different? (2) Where are these receptors located and what is their physiological function? (3) Can α-latrotoxin’s effects be explained by the receptor-activated intracellular
signaling?
