Kinetic studies on the interaction between botulinum toxin type A and the cholinergic neuromuscular junction.

Botulinum toxin-induced paralysis of neuromuscular transmission involves at least three steps. There is an initial binding step that is nontoxic, a translocation step that is nontoxic and a subsequent lytic step that produces blockade of transmission. In the absence of nerve stimulation, the binding step has a half-time of similar to or approximately 12 min and a rate constant of similar to or approximately 0.058 . min-1. The binding step does not require calcium or nerve stimulation, and it has a low temperature dependence (Q10 similar to or approximately 1.6). In the absence of nerve stimulation, the translocation step has a half-time of similar to or approximately 4.9 min and a rate constant of similar to or approximately 0.141 . min-1. Translocation requires physiological concentrations of calcium. In the virtual absence of nerve stimulation (1 x 10(-2) Hz), the lytic step has a half-time of similar to or approximately 55 min and a rate constant of similar to or approximately 0.013 . min-1. The lytic step requires calcium, is facillitated by nerve stimulation and has a high temperature dependence by nerve stimulation and has a high temperature dependence (Q10 similar to or approximately 4.2). These data are used to propose a model for botulinum toxin interaction with the cholinergic nerve terminal.