Botulinum Neurotoxins ADP-Ribosylate A Novel GTP-Binding Protein (Gb)

Abstract

Botulinum neurotoxin is an exotoxin produced by Clostridium botulinum which, when ingested, causes an acute and fatal poisoning characterized by progressive descending muscle paralysis (see review 1 and 2). There are several types of botulinum neurotoxins termed A, B, C1, D, E, F and G, which are distinct antigenically but similar in molecular size and structure. Pharmacologically all types of the toxin act similarly on various nerve endings, especially those of cholinergic nerves, and block the release of neurotransmitters. Though the exact mechanism of this action has not been clarified yet, Knight et al. (3), using permeabilized adrenal chromaffin cells in culture, have shown that the toxin acts on some target(s) downstream from calcium entry to the cells. Since virtually nothing is known about molecular events in the exocytotic process after the rise in free calcium ion concentration in cells, elucidation of a botulinum toxin target(s) would contribute to clarifying the mechanism of this basic cell function. A hypothesis that the botulinum neurotoxin is an enzyme has been proposed on the basis of its extreme potency and long duration of action (1,4). Recently we have found ADP-ribosyl transferase activity in types C1 and D botulinum neurotoxin (5, 6). Here we review these findings and present more detailed analyses on the target protein(s) and catalytic nature of this reaction. Our results are discussed in terms of the present knowledge on the mechanism of the exocytotic process.