4-Аminopyridine sequesters intracellular Ca(2+) which triggers exocytosis in excitable and non-excitable cells

4-aminopyridine is commonly used to stimulate neurotransmitter release resulting from sustained plasma membrane depolarization and Ca(2+)-influx from the extracellular space. This paper elucidated unconventional mechanism of 4-aminopyridine-stimulated glutamate release from neurons and non-neuronal cells which proceeds in the absence of external Ca(2+). In brain nerve terminals, primary neurons and platelets 4-aminopyridine induced the exocytotic release of glutamate that was independent of external Ca(2+) and was triggered by the sequestration of Ca(2+) from intracellular stores. The initial level of 4-aminopyridine-stimulated glutamate release from neurons in the absence or presence of external Ca(2+) was subequal and the difference was predominantly associated with subsequent tonic release of glutamate in Ca(2+)-supplemented medium. The increase in [Ca(2+)](i) and the secretion of glutamate stimulated by 4-aminopyridine in Ca(2+)-free conditions have resulted from Ca(2+) efflux from endoplasmic reticulum and were abolished by intracellular free Ca(2+) chelator BAPTA. This suggests that Ca(2+) sequestration plays a profound role in the 4-aminopyridine-mediated stimulation of excitable and non-excitable cells. 4-Aminopyridine combines the properties of depolarizing agent with the ability to sequester intracellular Ca(2+). The study unmasks additional mechanism of action of 4-aminopyridine, an active substance of drugs for treatment of multiple sclerosis and conditions related to reduced Ca(2+) efflux from intracellular stores.