Neurotoxins Affecting Neuroexocytosis

Imperial Cancer Research Fund, London, United Kingdom; Centro Consiglio Nazionale delle Ricerca di Farmacologia Molecolare e Cellulare e Centro "B. Ceccarelli," Dipartimento di Farmacologia, Università di Milano, Milan; and Centro Consiglio Nazionale delle Ricerca Biomembrane and Dipartimento di Scienze Biomediche, Università di Padova, Padua, Italy Schiavo, Giampietro, Michela Matteoli, and Cesare Montecucco. Neurotoxins Affecting Neuroexocytosis. Physiol. Rev. 80: 717-766, 2000. Nerve terminals are specific sites of action of a very large number of toxins produced by many different organisms. The mechanism of action of three groups of presynaptic neurotoxins that interfere directly with the process of neurotransmitter release is reviewed, whereas presynaptic neurotoxins acting on ion channels are not dealt with here. These neurotoxins can be grouped in three large families: 1 ) the clostridial neurotoxins that act inside nerves and block neurotransmitter release via their metalloproteolytic activity directed specifically on SNARE proteins; 2 ) the snake presynaptic neurotoxins with phospholipase A 2 activity, whose site of action is still undefined and which induce the release of acethylcholine followed by impairment of synaptic functions; and 3 ) the excitatory latrotoxin-like neurotoxins that induce a massive release of neurotransmitter at peripheral and central synapses. Their modes of binding, sites of action, and biochemical activities are discussed in relation to the symptoms of the diseases they cause. The use of these toxins in cell biology and neuroscience is considered as well as the therapeutic utilization of the botulinum neurotoxins in human diseases characterized by hyperfunction of cholinergic terminals.