GABA induces norepinephrine exocytosis from hippocampal noradrenergic axon terminals by a dual mechanism involving different voltage-sensitive calcium channels.
GABA can evoke norepinephrine (NE) release by activating GABAA receptors or GABA transporters on noradrenergic terminals. The heterocarrier-induced release occurs by conventional exocytosis. We here characterized the mechanism of the GABAA receptor-induced release and investigated what type(s) of voltage-sensitive Ca2+ channels (VSCCs) are involved in the GABA heterocarrier and GABA(A) receptor-evoked release. The effect of GABA in superfused rat hippocampal synaptosomes prelabeled with [(3)H]-NE was partially prevented by bicuculline or the GABA uptake inhibitor SKF 89976A and abolished by blocking both GABAA receptors and GABA transporters. The release elicited through GABAA receptors was Ca2+-dependent, prevented by Cd2+ or by botulinum toxin C, and modulated through alpha2 autoreceptors. The GABAA receptor-evoked release was insensitive to nifedipine and to omega-conotoxin MVIIC, but was inhibited ( approximately 50%) by omega-conotoxin GVIA. The heterocarrier-evoked release, nifedipine-insensitive, was inhibited approximately 30% either by omega-conotoxin GVIA or by omega-conotoxin MVIIC; the combined toxins produced approximately 60% inhibition. To conclude: a) the releases of NE evoked by activation of GABA(A) receptors and GABA heterocarriers are additive, although they both occur by conventional exocytosis; b) the heterocarrier-induced release requires activation of N and P/Q type channels, whereas the GABAA receptor-induced release only involves channels of the N type.
Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy.
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A
Fassio
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Rossi
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G
Bonanno
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Raiteri
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects*; D018682:GABA Agents / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D018682:GABA Agents; D058785:GABA-A Receptor Agonists; D009557:Nipecotic Acids; D011941:Receptors, Adrenergic; D005680:gamma-Aminobutyric Acid; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D009543:Nifedipine; D009638:Norepinephrine