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Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals
Author(s) -
Chang Yi,
Hsieh Hsi Lung,
Huang Shu Kuei,
Wang Su Jane
Publication year - 2019
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.22076
Subject(s) - allopregnanolone , glutamate receptor , chemistry , neuroactive steroid , excitotoxicity , pharmacology , channel blocker , endocrinology , medicine , calcium , receptor , biochemistry , gabaa receptor , biology , organic chemistry
Allopregnanolone, an active metabolite of progesterone, has been reported to exhibit neuroprotective activity in several preclinical models. Considering that the excitotoxicity caused by excessive glutamate is implicated in many brain disorders, the effect of allopregnanolone on glutamate release in rat cerebrocortical nerve terminals and possible underlying mechanism were investigated. We observed that allopregnanolone inhibited 4‐aminopyridine (4‐AP)‐evoked glutamate release, and this inhibition was prevented by chelating the extracellular Ca 2+ ions and the vesicular transporter inhibitor. Allopregnanolone reduced the elevation of 4‐AP‐evoked intrasynaptosomal Ca 2+ levels, but did not affect the synaptosomal membrane potential. In the presence of N‐, P/Q‐, and R‐type channel blockers, allopregnanolone‐mediated inhibition of 4‐AP‐evoked glutamate release was markedly reduced; however, the intracellular Ca 2+ ‐release inhibitors did not affect the allopregnanolone effect. Furthermore, allopregnanolone‐mediated inhibition of 4‐AP‐evoked glutamate release was completely abolished in the synaptosomes pretreated with inhibitors of Ca 2+ /calmodulin, adenylate cyclase, and protein kinase A (PKA), namely calmidazolium, MDL12330A, and H89, respectively. Additionally, the allopregnanolone effect on evoked glutamate release was antagonized by the GABA A receptor antagonist SR95531. Our data are the first to suggest that allopregnanolone reduce the Ca 2+ influx through N‐, P/Q‐, and R‐type Ca 2+ channels, through the activation of GABA A receptors present on cerebrocortical nerve terminals, subsequently suppressing the Ca 2+ ‐calmodulin/PKA cascade and decreasing 4‐AP‐evoked glutamate release.