title: 4-Аminopyridine sequesters intracellular Ca2+which triggers exocytosis in excitable and non-excitable cells.
abstract: 4-aminopyridine is commonly used to stimulate neurotransmitter release resulting from sustained plasma membrane depolarization and Ca2+-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 Ca2+. In brain nerve terminals, primary neurons and platelets 4-aminopyridine induced the exocytotic release of glutamate that was independent of external Ca2+and was triggered by the sequestration of Ca2+from intracellular stores. The initial level of 4-aminopyridine-stimulated glutamate release from neurons in the absence or presence of external Ca2+was subequal and the difference was predominantly associated with subsequent tonic release of glutamate in Ca2+-supplemented medium. The increase in [Ca2+]iand the secretion of glutamate stimulated by 4-aminopyridine in Ca2+-free conditions have resulted from Ca2+efflux from endoplasmic reticulum and were abolished by intracellular free Ca2+chelator BAPTA. This suggests that Ca2+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 Ca2+. 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 Ca2+efflux from intracellular stores.
authors.affiliation: The Department of Neurochemistry, Palladin Institute of Biochemistry, NAS of Ukraine 9, Leontovicha Street, Kyiv, 01030, Ukraine.
authors.forename: Ludmila A
authors.initials: LA
authors.lastname: Kasatkina
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005089:Exocytosis; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats
chemical_list: D026902:Potassium Channel Blockers; D018698:Glutamic Acid; D015761:4-Aminopyridine; D002118:Calcium