Protonophore antagonism of botulinum toxin in mouse muscle

Botulinum neurotoxins (BoNT) are thought to enter cells through endocytotic vesicles where acidification is required for release of these toxins into the cytoplasm. Two ionophores, nigericin and monensin, that increase membrane permeability to H+ and K+ or H+, Na+ and K+, respectively, block vesicle acidification by acting as H+ shunts to neutralize pH gradients. Nanomolar concentrations of nigericin or monensin delayed development of blockade in BoNT-A or BoNT-B treated muscles two- to threefold over onset times in unprotected muscles. However, higher concentrations of the ionophores directly blocked synapses. Thus, nigericin and monensin could delay onset of BoNT paralysis only over a narrow range of concentrations. Copyright (C) 1996 Elsevier Science Ltd