INTRODUCTION: We investigated the effects of 3,4-diaminopyridine (3,4-DAP) and its acetylated metabolite, N-(4-amino-pyridin-3-yl) acetamide (3-Ac), at the mammalian neuromuscular junction. METHODS: Quantal release of acetylcholine was studied in diaphragm muscles of mice, using in vitro intracellular microelectrode recordings. RESULTS: Under conditions of low probability of release, 3,4-DAP produced a 1,000% increase in quantal release, but 3-Ac had no effect. Under conditions of normal probability of release, the effect of 3,4-DAP was modest and limited by concurrent depletion of synaptic vesicles, especially with high concentrations of 3,4-DAP and high frequencies of nerve stimulation. CONCLUSIONS: These findings predict 3,4-DAP is most effective in conditions with low probability of quantal release, such as Lambert-Eaton myasthenic syndrome. A beneficial effect is also expected in disorders of neuromuscular transmission in which the effect of 3,4-DAP on quantal release is not limited by depletion of synaptic vesicles, such as postsynaptic congenital myasthenic syndromes. Muscle Nerve, 2016 Muscle Nerve 55: 223-231, 2017.
INTRODUCTION: We investigated the effects of 3,4-diaminopyridine (3,4-DAP) and its acetylated metabolite, N-(4-amino-pyridin-3-yl) acetamide (3-Ac), at the mammalian neuromuscular junction. METHODS: Quantal release of acetylcholine was studied in diaphragm muscles of mice, using in vitro intracellular microelectrode recordings. RESULTS: Under conditions of low probability of release, 3,4-DAP produced a 1,000% increase in quantal release, but 3-Ac had no effect. Under conditions of normal probability of release, the effect of 3,4-DAP was modest and limited by concurrent depletion of synaptic vesicles, especially with high concentrations of 3,4-DAP and high frequencies of nerve stimulation. CONCLUSIONS: These findings predict 3,4-DAP is most effective in conditions with low probability of quantal release, such as Lambert-Eaton myasthenic syndrome. A beneficial effect is also expected in disorders of neuromuscular transmission in which the effect of 3,4-DAP on quantal release is not limited by depletion of synaptic vesicles, such as postsynaptic congenital myasthenic syndromes. Muscle Nerve, 2016 Muscle Nerve 55: 223-231, 2017.
Authors: James B Machamer; Edwin J Vazquez-Cintron; Sean W O'Brien; Kyle E Kelly; Amber C Altvater; Kathleen T Pagarigan; Parker B Dubee; Celinia A Ondeck; Patrick M McNutt Journal: Mol Med Date: 2022-06-03 Impact factor: 6.376
Authors: Kristine S Ojala; Scott P Ginebaugh; Man Wu; Evan W Miller; Gloria Ortiz; Manuel Covarrubias; Stephen D Meriney Journal: J Biol Chem Date: 2021-01-17 Impact factor: 5.157
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