Long, P;
Mercer, A;
Begum, R;
Stephens, GJ;
Sihra, TS;
Jovanovic, JN;
(2009)
Nerve Terminal GABA(A) Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release.
J BIOL CHEM
, 284
(13)
8717 - 8728.
10.1074/jbc.M805322200.
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Abstract
gamma-Aminobutyric acid type A (GABA(A)) receptors, a family of Cl--permeable ion channels, mediate fast synaptic inhibition as postsynaptically enriched receptors for gamma-aminobutyric acid at GABAergic synapses. Here we describe an alternative type of inhibition mediated by GABA(A) receptors present on neocortical glutamatergic nerve terminals and examine the underlying signaling mechanism(s). By monitoring the activity of the presynaptic CaM kinase II/synapsin I signaling pathway in isolated nerve terminals, we demonstrate that GABAA receptor activation correlated with an increase in basal intraterminal [Ca2+](i). Interestingly, this activation of GABAA receptors resulted in a reduction of subsequent depolarization-evoked Ca2+ influx, which thereby led to an inhibition of glutamate release. To investigate how the observed GABAA receptor-mediated modulation operates, we determined the sensitivity of this process to the Na-K-2Cl cotransporter 1 antagonist bumetanide, as well as substitution of Ca2+ with Ba2+, or Ca2+/calmodulin inhibition by W7. All of these treatments abolished the modulation by GABAA receptors. Application of selective antagonists of voltage-gated Ca2+ channels (VGCCs) revealed that the GABA(A) receptor-mediated modulation of glutamate release required the specific activity of L- and R-type VGCCs. Crucially, the inhibition of release by these receptors was abolished in terminals isolated from R-type VGCC knock-out mice. Together, our results indicate that a functional coupling between nerve terminal GABA(A) receptors and L- or R-type VGCCs is mediated by Ca2+/calmodulin-dependent signaling. This mechanism provides a GABA-mediated control of glutamatergic synaptic activity by a direct inhibition of glutamate release.
| Type: | Article |
|---|---|
| Title: | Nerve Terminal GABA(A) Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.M805322200 |
| Publisher version: | http://dx.doi.org/10.1074/jbc.M805322200 |
| Language: | English |
| Additional information: | © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | PRESYNAPTIC IONOTROPIC RECEPTORS, CALCIUM-CHANNELS, TRANSMITTER RELEASE, PROTEIN-KINASE, SYNAPSIN-I, CALMODULIN ANTAGONISTS, CHLORIDE CONCENTRATION, SYNAPTIC-TRANSMISSION, HIPPOCAMPAL-NEURONS, CA(V)2.1 CHANNELS |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1341390 |
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