GABA induces norepinephrine exocytosis from hippocampal noradrenergic axon terminals by a dual mechanism involving different voltage-sensitive calcium channels

Abstract

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.