title: Flunarizine inhibits both calcium-dependent and -independent release of glutamate from synaptosomes and cultured neurones.
abstract: Flunarizine, an established Ca2+ channel antagonist, blocks both exocytotic glutamate release from mammalian cultured cerebellar granule cells and isolated presynaptic nerve endings (synaptosomes) prepared from two distinct areas of the mammalian brain. This blockade of release displays the same flunarizine concentration dependency in synaptosomes in the presence or absence of Ca2+, with total inhibition at a concentration of 10 microM. In cultured neurones, a selective effect on the L-channel-coupled component of the KCl-evoked rise in intracellular Ca2+, [Ca2+]c, can be demonstrated between flunarizine concentrations of 100 nM and 10 microM, while at concentrations above 10 microM, the remaining residual and transient components are affected. In synaptosomes, flunarizine blocks the KCl-evoked elevation in [Ca2+]c in a concentration-dependent manner. Additionally, 10 microM flunarizine directly antagonises ouabain-induced tetrodotoxin (TTX)-sensitive Na+ influx, glutamate, aspartate and GABA release from synaptosomes, whilst inhibiting veratridine-induced Ca(2+)-independent TTX-sensitive Na+ influx and glutamate release at 15 microM and 10 microM in cells and synaptosomes, respectively. In both cultured neurones and synaptosomes, the ability of flunarizine to block both neurotransmitter and cytoplasmic glutamate release is due to a direct antagonism of both voltage dependent Ca2+ channels and tetrodotoxin-sensitive Na+ channels.
authors.affiliation: Department of Biochemistry, University of Dundee, Scotland, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Cousin
authors.forename: D G
authors.initials: DG
authors.lastname: Nicholls
authors.forename: J M
authors.initials: JM
authors.lastname: Pocock
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists; D005444:Flunarizine / Q000494:pharmacology*; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009994:Osmolar Concentration; D010042:Ouabain / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018377:Neurotransmitter Agents; D018698:Glutamic Acid; D013779:Tetrodotoxin; D010042:Ouabain; D011189:Potassium Chloride; D014701:Veratridine; D005444:Flunarizine; D002118:Calcium