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    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 GABA(A) receptor activation correlated with an increase in basal intraterminal [Ca(2+)](i). Interestingly, this activation of GABA(A) receptors resulted in a reduction of subsequent depolarization-evoked Ca(2+) influx, which thereby led to an inhibition of glutamate release. To investigate how the observed GABA(A) 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 Ca(2+) with Ba(2+), or Ca(2+)/calmodulin inhibition by W7. All of these treatments abolished the modulation by GABA(A) receptors. Application of selective antagonists of voltage-gated Ca(2+) 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 Ca(2+)/calmodulin-dependent signaling. This mechanism provides a GABA-mediated control of glutamatergic synaptic activity by a direct inhibition of glutamate release.


    Philip Long, Audrey Mercer, Rahima Begum, Gary J Stephens, Talvinder S Sihra, Jasmina N Jovanovic. Nerve Terminal GABAA Receptors Activate Ca2+/Calmodulin-dependent Signaling to Inhibit Voltage-gated Ca2+ Influx and Glutamate Release. The Journal of biological chemistry. 2009 Mar 27;284(13):8726-37

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    PMID: 19141616

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