title: GABA release provoked by disturbed Na(+), K(+) and Ca(2+) homeostasis in cerebellar nerve endings: roles of Ca(2+) channels, Na(+)/Ca(2+) exchangers and GAT1 transporter reversal.
abstract: GABA release provoked by ion dysregulations typical of some neuropathological conditions was analyzed in purified cerebellar synaptosomes pre-labeled with [(3)H]GABA and exposed in superfusion to KCl, 4-aminopyridine (4-AP) or veratridine. The overflows caused by relatively low concentrations of the releasers were almost totally external Ca(2+)-dependent. Higher concentrations of KCl or veratridine, but not 4-AP, involved also external Ca(2+)-independent mechanisms. The GABA overflows evoked by veratridine and, less so, the overflow evoked by high K(+), occurred in part by reversal of the GAT1 transporter. None of the depolarizing agents activated store-operated or transient receptor potential or L-type Ca(2+) channels. Only the overflow caused by 4-AP occurred in part by N- and P/Q-type voltage-sensitive calcium channel-dependent exocytosis. Significant portions of the external Ca(2+)-dependent overflows evoked by the three releasers involved reversal of plasmalemmal Na(+)/Ca(2+) exchangers. The overflows evoked by high K(+) or veratridine, but not by 4-AP were evoked by Ca(2+) originated through mitochondrial Na(+)/Ca(2+) exchangers. Ca(2+)-induced Ca(2+) release mediated by inositoltrisphosphate receptors participated exclusively in the GABA release stimulated by high KCl which also occurred in a modest portion through anion channels. Important differences could be observed between the release mechanisms of GABA here described and those previously reported for glycine, in spite of the abundant vesicular co-localization of the two transmitters in cerebellar interneurons.
authors.affiliation: Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Romei
authors.affiliation: Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Sabolla
authors.affiliation: Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy; Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy; National Institute of Neuroscience, Genoa, Italy. Electronic address: lraiter@pharmatox.unige.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Raiteri
mesh_terms: D000818:Animals; D029681:Arabidopsis Proteins; D002118:Calcium / Q000378:metabolism*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050485:GABA Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D026901:Membrane Transport Proteins; D051379:Mice; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D029681:Arabidopsis Proteins; D050485:GABA Plasma Membrane Transport Proteins; C510128:GAT1 protein, Arabidopsis; D026901:Membrane Transport Proteins; D026902:Potassium Channel Blockers; D019831:Sodium-Calcium Exchanger; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D014701:Veratridine; D012964:Sodium; D011188:Potassium; D002118:Calcium
keywords: Eexocytosis; GABA release; GAT1 transporter reversal; InsP(3) receptors; Mouse cerebellum; Na(+)/Ca(2+) exchangers