Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

Long, Philip; Mercer, Audrey; Begum, Rahima; Stephens, Gary J.; Sihra, Talvinder S.; Jovanovic, Jasmina N.

doi:10.1074/jbc.m805322200

Cited by 37 publications

(24 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the presence of nifedipine, allopregnanolone (20 μM) inhibited the 4‐AP‐induced release of glutamate by 59.3% ± 3.5%, which was not significantly different from the inhibition achieved using allopregnanolone alone (59.4% ± 4.2%; p > 0.05; Figures and ). Similar results were observed with NiCl 2 at the 50 µM concentration that selectively blocks T‐type Ca 2+ channels (Long et al, ). Figure e shows that 4‐AP‐evoked glutamate release under control conditions was unaffected by NiCl 2 .…”

Section: Resultssupporting

confidence: 84%

Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals

Chang

Hsieh

Huang

et al. 2018

Synapse

View full text Add to dashboard Cite

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 Ca2+ ions and the vesicular transporter inhibitor. Allopregnanolone reduced the elevation of 4‐AP‐evoked intrasynaptosomal Ca2+ 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 Ca2+‐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 Ca2+/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 GABAA receptor antagonist SR95531. Our data are the first to suggest that allopregnanolone reduce the Ca2+ influx through N‐, P/Q‐, and R‐type Ca2+ channels, through the activation of GABAA receptors present on cerebrocortical nerve terminals, subsequently suppressing the Ca2+‐calmodulin/PKA cascade and decreasing 4‐AP‐evoked glutamate release.

show abstract

Section: Resultssupporting

confidence: 84%

Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals

Chang

Hsieh

Huang

et al. 2018

Synapse

View full text Add to dashboard Cite

show abstract

“…Synaptosomes were centrifuged in the final wash to obtain synaptosomal pellets with 0.5 mg protein. Synaptosomal pellets were stored on ice and used within 1–2 h. We have shown this well established preparation to be enriched in synapsin I, a exclusively presynaptic marker [12]. Further the robust metabolic competence and ability of percoll purified synaptosomes to release neurotransmitters [13,14], has made this preparation a persuasive model for elucidating presynaptic receptor function [15].…”

Section: Methodsmentioning

confidence: 99%

Presynaptic kainate receptor‐mediated facilitation of glutamate release involves Ca²⁺–calmodulin and PKA in cerebrocortical synaptosomes

Rodríguez‐Moreno

Sihra

2013

FEBS Letters

Self Cite

View full text Add to dashboard Cite

show abstract

“…Reports have suggested a close relationship between brain glutamatergic and GABAergic systems in the regulation of behavioral processes in that the GABA A receptor regulates glutamate release from a population of neocortical glutamatergic neurons by their own presynaptic receptors (Long et al, 2009). For instance, GABA A receptor stimulation was reported to exert a protective action against the neuronal injury induced by activation of NMDA receptors (Ohkuma et al, 1994).…”

Section: The Effect Of Muscimol or Bicuculline On Behaviors Induced Bmentioning

confidence: 99%

Involvement of the CA1 GABAA receptors in MK-801-induced anxiolytic-like effects

Naseri

Tackallou

Nami

et al. 2014

Behavioural Pharmacology

View full text Add to dashboard Cite

There seems to be a close relationship between hippocampal N-methyl-D-aspartic acid (NMDA) and GABAA receptors with respect to the modulation of behavior that occurs in the CA1 region of the hippocampus. This study investigated the possible involvement of the CA1 GABAA receptors in anxiolytic-like effects induced by (+)-MK-801 (a noncompetitive antagonist of the NMDA subtype of the glutamate receptor). Male Wistar rats were subjected to the elevated plus-maze apparatus and open arm time (%OAT), and open arm entries (%OAE) for anxiety-related behaviors, and closed arm entries that correspond to the locomotor activity were assessed. An intra-CA1 injection of (+)-MK-801 (2 μg/rat) and muscimol (0.5 μg/rat; a GABAA receptor agonist) increased %OAT and %OAE by themselves while not altering the closed arm entries, indicating an anxiolytic-like effect of these drugs. Injection of bicuculline (0.1, 0.25, and 0.5 μg/rat; a GABAA receptor antagonist) did not alter any of the anxiety-related parameters. An intra-CA1 injection of a subthreshold dose of muscimol (0.1 μg/rat) or bicuculline (0.5 μg/rat), 5 min before injection of subthreshold and effective doses of (+)-MK-801 (0.5, 1 and 2 μg/rat), increased and decreased the anxiolytic-like effect of (+)-MK-801, respectively. The isobologram analysis of these findings suggested a synergistic anxiety-like effect of intra-CA1 (+)-MK-801 and muscimol. In conclusion, the CA1 GABAA receptors appear to be involved in anxiolytic-like behaviors induced by (+)-MK-801.

show abstract

Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

Cited by 37 publications

References 88 publications

Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals

Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals

Presynaptic kainate receptor‐mediated facilitation of glutamate release involves Ca²⁺–calmodulin and PKA in cerebrocortical synaptosomes

Involvement of the CA1 GABAA receptors in MK-801-induced anxiolytic-like effects

Contact Info

Product

Resources

About

Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release

Cited by 37 publications

References 88 publications

Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals

Neurosteroid allopregnanolone inhibits glutamate release from rat cerebrocortical nerve terminals

Presynaptic kainate receptor‐mediated facilitation of glutamate release involves Ca2+–calmodulin and PKA in cerebrocortical synaptosomes

Involvement of the CA1 GABAA receptors in MK-801-induced anxiolytic-like effects

Contact Info

Product

Resources

About

Presynaptic kainate receptor‐mediated facilitation of glutamate release involves Ca²⁺–calmodulin and PKA in cerebrocortical synaptosomes