Pre-synaptic kainate receptor-mediated facilitation of glutamate release involves PKA and Ca(2+) -calmodulin at thalamocortical synapses.

We have investigated the mechanisms underlying the facilitatory modulation mediated by kainate receptor (KAR) activation in the cortex, using isolated nerve terminals (synaptosomes) and slice preparations. In cortical nerve terminals, kainate (KA, 100 µM) produced an increase in 4-aminopyridine (4-AP)-evoked glutamate release. In thalamocortical slices, KA (1 µM) produced an increase in the amplitude of evoked excitatory post-synaptic currents (eEPSCs) at synapses established between thalamic axon terminals from the ventrobasal nucleus onto stellate neurons of L4 of the somatosensory cortex. In both, synaptosomes and slices, the effect of KA was antagonized by 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted after pre-treatment with a cocktail of antagonists of other receptors whose activation could potentially have produced facilitation of release indirectly. Mechanistically, the observed effects of KA appear to be congruent in synaptosomal and slice preparations. Thus, the facilitation by KA of synaptosomal glutamate release and thalamocortical synaptic transmission were suppressed by the inhibition of protein kinase A and occluded by the stimulation of adenylyl cyclase. Dissecting this G-protein-independent regulation further in thalamocortical slices, the KAR-mediated facilitation of synaptic transmission was found to be sensitive to the block of Ca(2+) permeant KARs by philanthotoxin. Intriguingly, the synaptic facilitation was abrogated by depletion of intracellular Ca(2+) stores by thapsigargin, or inhibition of Ca(2+) -induced Ca(2+) -release by ryanodine. Thus, the KA-mediated modulation was contingent on both Ca(2+) entry through Ca(2+) -permeable KARs and liberation of intracellular Ca(2+) stores. Finally, sensitivity to W-7 indicated that the increased cytosolic [Ca(2+) ] underpinning KAR-mediated regulation of synaptic transmission at thalamocortical synapses, requires downstream activation of calmodulin. We conclude that neocortical pre-synaptic KARs mediate the facilitation of glutamate release and synaptic transmission by a Ca(2+) -calmodulin dependent activation of an adenylyl cyclase/cAMP/protein kinase A signalling cascade, independent of G-protein involvement.

Positive feedback regulation between gamma-aminobutyric acid type A (GABA(A)) receptor signaling and brain-derived neurotrophic factor (BDNF) release in developing neurons.

During the early development of the nervous system, γ-aminobutyric acid (GABA) type A receptor (GABA(A)R)-mediated signaling parallels the neurotrophin/tropomyosin-related kinase (Trk)-dependent signaling in controlling a number of processes from cell proliferation and migration, via dendritic and axonal outgrowth, to synapse formation and plasticity. Here we present the first evidence that these two signaling systems regulate each other through a complex positive feedback mechanism. We first demonstrate that GABA(A)R activation leads to an increase in the cell surface expression of these receptors in cultured embryonic cerebrocortical neurons, specifically at the stage when this activity causes depolarization of the plasma membrane and Ca(2+) influx through L-type voltage-gated Ca(2+) channels. We further demonstrate that GABA(A)R activity triggers release of the brain-derived neurotrophic factor (BDNF), which, in turn by activating TrkB receptors, mediates the observed increase in cell surface expression of GABA(A)Rs. This BDNF/TrkB-dependent increase in surface levels of GABA(A)Rs requires the activity of phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC) and does not involve the extracellular signal-regulated kinase (ERK) 1/2 activity. The increase in GABA(A)R surface levels occurs due to an inhibition of the receptor endocytosis by BDNF, whereas the receptor reinsertion into the plasma membrane remains unaltered. Thus, GABA(A)R activity is a potent regulator of the BDNF release during neuronal development, and at the same time, it is strongly enhanced by the activity of the BDNF/TrkB/PI3K/PKC signaling pathway.

Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+ -calmodulin at mossy fiber-CA3 synapses.

Presynaptic kainate receptors (KARs) modulate the release of glutamate at synapses established between mossy fibers (MF) and CA3 pyramidal cells in the hippocampus. The activation of KAR by low, nanomolar, kainate concentrations facilitates glutamate release. KAR-mediated facilitation of glutamate release involves the activation of an adenylate cyclase/cyclic adenosine monophosphate/protein kinase A cascade at MF-CA3 synapses. Here, we studied the mechanisms by which KAR activation produces this facilitation of glutamate release in slices and synaptosomes. We find that the facilitation of glutamate release mediated by KAR activation requires an increase in Ca(2+) levels in the cytosol and the formation of a Ca(2+) -calmodulin complex to activate adenylate cyclase. The increase in cytosolic Ca(2+) underpinning this modulation is achieved, both, by Ca(2+) entering via Ca(2+) -permeable KARs and, by the mobilization of intraterminal Ca(2+) stores. Finally, we find that, congruent with the Ca(2+) -calmodulin support of KAR-mediated facilitation of glutamate release, induction of long-term potentiation at MF-CA3 synapses has an obligate requirement for Ca(2+) -calmodulin activity.

Loss of phosphatidylinositol 4-kinase 2alpha activity causes late onset degeneration of spinal cord axons.

Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase and phosphatase activities. Although many signaling roles of PI kinases have been identified in cultured cell lines, transgenic animal studies have produced unexpected insight into the in vivo functions of specific PI 3- and 5-kinases, but no mammalian PI 4-kinase (PI4K) knockout has previously been reported. Prior studies using cultured cells implicated the PI4K2alpha isozyme in diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, and regulated secretion. We now show that despite these important functions, mice lacking PI4K2alpha kinase activity initially appear normal. However, adult Pi4k2a(GT/GT) animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged Pi4k2a(GT/GT) animals revealed lipofuscin-like deposition and gliosis in the cerebellum, and loss of Purkinje cells. Peripheral nerves are essentially normal, but massive axonal degeneration was found in the spinal cord in both ascending and descending tracts. These results reveal a previously undescribed role for aberrant PI signaling in neurological disease that resembles autosomal recessive hereditary spastic paraplegia.

Metabotropic actions of kainate receptors in the control of glutamate release in the hippocampus.

Kainate-type glutamate receptors (KARs) structurally present the credentials of the other ionotropic glutamate receptor (iGluR) family members (NMDA and AMPA receptors), but functionally often purport examples of a metabotropic mode of operation. In the present chapter, we describe these metabotropic roles of KARs in the modulation of glutamate release in the hippocampus at CA3 Schaffer Collateral (SC)-CA1 Pyramidal Cell (PC) synapses and dentate gyrus granule cell Mossy Fiber (MF)-CA3 PC synapses. As autoreceptors on SC terminals, KARs inhibit the release of glutamate at SC-CA1 PC synapses through a mechanism dependent on a pertussis toxin-sensitive G(i/o) protein thought to couple via its Gßγ subunit to a decrease in Ca(2+) channel function. At MF-CA3 PC synapses, autoreceptors on MF terminals respond diametrically depending on the agonist concentration. At low KA concentrations (< 100 nM), a G-protein-independent process invokes the activation of proteins kinase A (PKA) to effect a facilitation of glutamate release. This facilitation possibly involves the Ca(2+)-dependent (rather than GPCR-dependent) activation of adenylate cyclase (AC). At high KA concentrations (<100 nM), a mechanism involving a pertussis toxin-sensitive G(i/o) protein is invoked to inhibit AC activity and thereby suppress PKA activity. Taken together with the heterosynaptic regulation of GABA release by KARs working with a metabotropic modus operandi, there is therefore compelling evidence that these ionotropic glutamate receptors are involved in a noncanonical modulation of glutamate release that does not rely on their typical ionotropic activity.

Metabotropic actions of kainate receptors in the control of GABA release.

Kainate receptors (KARs) are members of the family of ionotropic glutamate receptors (iGluRs) which also include NMDA and AMPA receptors. As ionotropic receptors, KARs have been characterized, pre and postsynaptically, in several brain regions. In this chapter we review evidence that suggests that KARs mediate some of their effects without invoking ion-fluxes. Beginning with seminal experiments described some ten years ago, when the notion of a metabotropic action of KAR was first posited in the modulation of GABA release from hippocampal interneurons, increasingly, there have been reports indicating that some KAR functions overtly depend on G-protein activation and involve the participation of intracellular signalling cascades. Thus, KAR activation instigates a cascade involving G(i/o), phospholipase C and protein kinase C to suppress the release of GABA and therefore underpins disinhibition of pyramidal cells in the CA1 region of the hippocampus. This type of metabotropic function of KARs in controlling GABA release represents an additional level of activity-dependent control of synaptic inhibition which is independent of any ionotropic activity of KARs.

Presynaptic roles of intracellular Ca(2+) stores in signalling and exocytosis.

The signalling roles of Ca(2+)(ic) (intracellular Ca(2+)) stores are well established in non-neuronal and neuronal cells. In neurons, although Ca(2+)(ic) stores have been assigned a pivotal role in postsynaptic responses to G(q)-coupled receptors, or secondarily to extracellular Ca(2+) influx, the functions of dynamic Ca(2+)(ic) stores in presynaptic terminals remain to be fully elucidated. In the present paper, we review some of the recent evidence supporting an involvement of Ca(2+)(ic) in presynaptic function, and discuss loci at which this source of Ca(2+) may impinge. Nerve terminal preparations provide good models for functionally examining putative Ca(2+)(ic) stores under physiological and pathophysiological stimulation paradigms, using Ca(2+)-dependent activation of resident protein kinases as sensors for fine changes in intracellular Ca(2+) levels. We conclude that intraterminal Ca(2+)(ic) stores may, directly or indirectly, enhance neurotransmitter release following nerve terminal depolarization and/or G-protein-coupled receptor activation. During conditions that prevail following neuronal ischaemia, increased glutamate release instigated by Ca(2+)(ic) store activation may thereby contribute to excitotoxicity and eventual synaptopathy.

Kainate receptors with a metabotropic modus operandi.

Kainate receptors (KARs), together with AMPA and NMDA, are typically described as ionotropic glutamate receptors. The functions of KARs have begun to be elucidated only in the last decade. Although some the actions of KARs are classically ionotropic, surprisingly others seem to involve the activation of second-messenger cascades and invoke metabotropic roles for this type of glutamate receptor. In this review, we describe these metabotropic actions of KARs in relation to the putative signalling cascades involved. Although it is still a mystery how KARs activate G proteins to stimulate second-messenger cascades, intriguingly, in very recent studies, specific subunits of KARs have been demonstrated to associate with G proteins. Altogether, the body of evidence supports the hypothesis that, together with the canonical ionotropic operation, KARs expedite long-lasting signalling by novel metabotropic modes of action.

Presynaptic signaling by heterotrimeric G-proteins.

G-proteins (guanine nucleotide-binding proteins) are membrane-attached proteins composed of three subunits, alpha, beta, and gamma. They transduce signals from G-protein coupled receptors (GPCRs) to target effector proteins. The agonistactivated receptor induces a conformational change in the G-protein trimer so that the alpha-subunit binds GTP in exchange for GDP and alpha-GTP, and betagamma-subunits separate to interact with the target effector. Effector-interaction is terminated by the alpha-subunit GTPase activity, whereby bound GTP is hydrolyzed to GDP. This is accelerated in situ by RGS proteins, acting as GTPase-activating proteins (GAPs). Galpha-GDP and Gbetagamma then reassociate to form the Galphabetagamma trimer. G-proteins primarily involved in the modulation of neurotransmitter release are G(o), G(q) and G(s). G(o) mediates the widespread presynaptic auto-inhibitory effect of many neurotransmitters (e.g., via M2/M4 muscarinic receptors, alpha(2) adrenoreceptors, micro/delta opioid receptors, GABAB receptors). The G(o) betagamma-subunit acts in two ways: first, and most ubiquitously, by direct binding to CaV2 Ca(2+) channels, resulting in a reduced sensitivity to membrane depolarization and reduced Ca(2+) influx during the terminal action potential; and second, through a direct inhibitory effect on the transmitter release machinery, by binding to proteins of the SNARE complex. G(s) and G(q) are mainly responsible for receptor-mediated facilitatory effects, through activation of target enzymes (adenylate cyclase, AC and phospholipase-C, PLC respectively) by the GTP-bound alpha-subunits.

Kainate Receptors: Role in Epilepsy.

Kainate (KA) is a potent neurotoxin that has been widely used experimentally to induce acute brain seizures and, after repetitive treatments, as a chronic model of temporal lobe epilepsy (TLE), with similar features to those observed in human patients with TLE. However, whether KA activates KA receptors (KARs) as an agonist to mediate the induction of acute seizures and/or the chronic phase of epilepsy, or whether epileptogenic effects of the neurotoxin are indirect and/or mediated by other types of receptors, has yet to be satisfactorily elucidated. Positing a direct involvement of KARs in acute seizures induction, as well as a direct pathophysiological role of KARs in the chronic phase of TLE, recent studies have examined the specific subunit compositions of KARs that might underly epileptogenesis. In the present mini-review, we discuss the use of KA as a convulsant in the experimental models of acute seizures of TLE, and consider the involvement of KARs, their subunit composition and the mode of action in KAR-mediated epilepsy. In acute models, evidence points to epileptogenesis being precipitated by an overall depression of interneuron GABAergic transmission mediated by GluK1 containing KARs. On glutamatergic principal cell in the hippocampus, GluK2-containing KARs regulate post-synaptic excitability and susceptibility to KA-mediated epileptogenesis. In chronic models, a role GluK2-containing KARs in the hippocampal CA3 region provokes limbic seizures. Also observed in the hippocampus, is a 'reactive plasticity', where MF sprouting is seen with target granule cells at aberrant synapses recruiting de novo GluR2/GluR5 heteromeric KARs. Finally, in human epilepsy and animal models, astrocytic expression of GluK1, 2, 4, and 5 is reported.

Cerebellar Kainate Receptor-Mediated Facilitation of Glutamate Release Requires Ca2+-Calmodulin and PKA.

We elucidated the mechanisms underlying the kainate receptor (KAR)-mediated facilitatory modulation of synaptic transmission in the cerebellum. In cerebellar slices, KA (3 µM) increased the amplitude of evoked excitatory postsynaptic currents (eEPSCs) at synapses between axon terminals of parallel fibers (PF) and Purkinje neurons. KA-mediated facilitation was antagonized by NBQX under condition where AMPA receptors were previously antagonized. Inhibition of protein kinase A (PKA) suppressed the effect of KA on glutamate release, which was also obviated by the prior stimulation of adenylyl cyclase (AC). KAR-mediated facilitation of synaptic transmission was prevented by blocking Ca2+ permeant KARs using philanthotoxin. Furthermore, depletion of intracellular Ca2+ stores by thapsigargin, or inhibition of Ca2+-induced Ca2+-release by ryanodine, abrogated the synaptic facilitation by KA. Thus, the KA-mediated modulation was conditional on extracellular Ca2+ entry through Ca2+-permeable KARs, as well as and mobilization of Ca2+ from intracellular stores. Finally, KAR-mediated facilitation was sensitive to calmodulin inhibitors, W-7 and calmidazolium, indicating that the increased cytosolic [Ca2+] sustaining KAR-mediated facilitation of synaptic transmission operates through a downstream Ca2+/calmodulin coupling. We conclude that, at cerebellar parallel fiber-Purkinje cell synapses, presynaptic KARs mediate glutamate release facilitation, and thereby enhance synaptic transmission through Ca2+-calmodulin dependent activation of adenylyl cyclase/cAMP/protein kinase A signaling.

Non-canonical Mechanisms of Presynaptic Kainate Receptors Controlling Glutamate Release.

A metabotropic modus operandi for kainate receptors (KARs) was first discovered in 1998 modulating GABA release. These receptors have been also found to modulate glutamate release at different synapses in several brain regions. Mechanistically, a general biphasic mechanism for modulating glutamate release by presynaptic KARs with metabotropic actions has emerged, with low KA concentrations invoking an increase in glutamate release, whereas higher concentrations of KA mediate a decrease in the release of this neurotransmitter. The molecular mechanisms underpinning the opposite modulation of glutamate release are distinct, with a G-protein-independent, adenylate cyclase (AC)- and protein kinase A (PKA)-dependent mechanism mediating the facilitation of glutamate release, while a G-protein dependent mechanism (with or without protein kinase recruitment) is involved in the decrease of neurotransmitter release. In the present review, we revisit the mechanisms underlying the non-canonical modus operandi of KARs effecting the bimodal control of glutamatergic transmission in different brain regions, and address the possible functions that this modulation may support.

Metabotropic actions of kainate receptors in the CNS.

Kainate receptors (KARs), together with NMDA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPA), are typically described as ionotropic glutamate receptors. Although ionotropic functions for KARs are beginning to be characterized in multiple brain regions, both, in the pre- and post-synaptic compartments of the synapse, there is accumulating evidence that KARs mediate some of their effects without invoking ion-fluxes. Thus, since 1998, when the first metabotropic action of KARs was described in the modulation of GABA release in hippocampal interneurons, there have been increasing reports that some of the functions of KARs involve the participation of intracellular signalling cascades and depend on G protein activation. These surprising observations, attesting metabotropic actions of KARs, akin to those usually attributed to seven transmembrane region G protein-coupled receptors, make the physiological classification and description of glutamate receptors more complex. In the present review, we describe the metabotropic roles of KARs in the CNS and discuss the intriguing properties of this receptor which, structurally shows all the facets of a typical ionotropic receptor, but appears to express a metabotropic remit at some key synapses.

GABAA receptor activity shapes the formation of inhibitory synapses between developing medium spiny neurons.

Basal ganglia play an essential role in motor coordination and cognitive functions. The GABAergic medium spiny neurons (MSNs) account for ~95% of all the neurons in this brain region. Central to the normal functioning of MSNs is integration of synaptic activity arriving from the glutamatergic corticostriatal and thalamostriatal afferents, with synaptic inhibition mediated by local interneurons and MSN axon collaterals. In this study we have investigated how the specific types of GABAergic synapses between the MSNs develop over time, and how the activity of GABAA receptors (GABAARs) influences this development. Isolated embryonic (E17) MSNs form a homogenous population in vitro and display spontaneous synaptic activity and functional properties similar to their in vivo counterparts. In dual whole-cell recordings of synaptically connected pairs of MSNs, action potential (AP)-activated synaptic events were detected between 7 and 14 days in vitro (DIV), which coincided with the shift in GABAAR operation from depolarization to hyperpolarization, as detected indirectly by intracellular calcium imaging. In parallel, the predominant subtypes of inhibitory synapses, which innervate dendrites of MSNs and contain GABAAR α1 or α2 subunits, underwent distinct changes in the size of postsynaptic clusters, with α1 becoming smaller and α2 larger over time, while both the percentage and the size of mixed α1/α2-postsynaptic clusters were increased. When activity of GABAARs was under chronic blockade between 4-7 DIV, the structural properties of these synapses remained unchanged. In contrast, chronic inhibition of GABAARs between 7-14 DIV led to reduction in size of α1- and α1/α2-postsynaptic clusters and a concomitant increase in number and size of α2-postsynaptic clusters. Thus, the main subtypes of GABAergic synapses formed by MSNs are regulated by GABAAR activity, but in opposite directions, and thus appear to be driven by different molecular mechanisms.

Presynaptic cross-talk of beta-adrenoreceptor and 5-hydroxytryptamine receptor signalling in the modulation of glutamate release from cerebrocortical nerve terminals.

1. The presynaptic interactions between facilitatory beta-adrenoreceptors and inhibitory 5-hydroxytryptamine (5-HT) receptors modulating glutamate release from cerebrocortical nerve terminals were examined. 2. 4-aminopyridine (4-AP, 1 mM)-evoked glutamate release was facilitated by the membrane permeant cyclic-3',5'-adenosine monophosphate (cAMP) analogue, 8-bromo-cAMP (8-Br-cAMP), used to directly activate cAMP-dependent protein kinase (PKA). 3. The beta-adrenoreceptor agonist, isoprenaline (ISO), effected a concentration-dependent potentiation of 4-AP-evoked glutamate release which was abolished by the beta-adrenoreceptor antagonist, propranolol, and the PKA inhibitor, Rp-cyclic-3',5'-adenosine-monophosphothioate (Rp-cAMPS). 4. 5-HT receptor activation by 100 microM 5-HT produced an inhibition of 4-AP-evoked glutamate release in nerve terminals. The inhibitory effect of 5-HT could be mimicked by the selective 5-HT(1A) receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) and antagonized by 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN-190). 5. When 5-HT (or 8-OH-DPAT) was used in conjunction with ISO or 8-Br-cAMP, the beta-adrenoreceptor- and PKA-mediated potentiation of glutamate release was abrogated. 6. The inhibitory crosstalk of 5-HT(1A) receptors to beta-adrenoceptor-mediated facilitation of glutamate release was abolished in the presence of NAN-190. 7. Examination of voltage-dependent Ca(2+) influx revealed that, while ISO and 5-HT alone caused a respective potentiation and diminution of the 4-AP-evoked increase in [Ca(2+)](c), the co-presence of 5-HT abolished the ISO mediated potentiation of Ca(2+) influx. 8. Together, these results suggest that beta-adrenoreceptors and 5-HT(1A) receptors coexist on the cerebrocortical nerve terminals and that the cross-talk between the two receptor signalling pathways occurs at a locus downstream from cAMP production, possibly at the level of voltage-dependent Ca(2+) influx.

Kainate receptors: multiple roles in neuronal plasticity.

Ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA)- and AMPA-type, as well as metabotropic glutamate receptors have been extensively invoked in plasticity. Until relatively recently, however, kainate-type receptors (KARs) had been the most elusive to study because of the lack of appropriate pharmacological tools to specifically address their roles. With the development of selective glutamate receptor antagonists, and knockout mice with specific KAR subunits deleted, the functions of KARs in neuromodulation and synaptic transmission, together with their involvement in some types of plasticity, have been extensively probed in the central nervous system. In this review, we summarize the findings related to the roles of KARs in short- and long-term forms of plasticity, primarily in the hippocampus, where KAR function and synaptic plasticity have received avid attention.

Presynaptic kainate receptor-mediated bidirectional modulatory actions: mechanisms.

Kainate receptors (KARs) are members of the glutamate receptor family, which also includes two other ionotropic subtypes, i.e. NMDA- and AMPA-type receptors, and types I, II and III metabotropic glutamate receptors. KARs mediate synaptic transmission postynaptically through their ionotropic capacity, while presynaptically, they modulate the release of both GABA and glutamate through operationally diverse modus operandi. At hippocampal mossy fiber (MF)-CA3 synapses, KARs have a biphasic effect on glutamate release, such that, depending on the extent of their activation, a facilitation or depression of glutamate release can be observed. This modulation is posited to contribute to important roles of KARs in short- and long-term plasticity. Elucidation of the modes of action of KARs in their depression and facilitation of glutamate release is beginning to gather impetus. Here we will focus on the cellular mechanisms involved in the modulation of glutamate release by presynaptic KAR activation at MF-CA3 synapses, a field that has seen significant progress in recent years.

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

We have explored the mechanisms involved in the facilitation of glutamate release mediated by the activation of kainate receptors (KARs) in the cortex using isolated nerve terminals (synaptosomes). Kainate (KA) produced an increase on glutamate release at 100 µM. The effect of KA was antagonized by NBQX (with AMPA receptors blocked by GYKI53655). This facilitation was suppressed by the inhibition of PKA activation by Rp-Br-cAMP and H-89. Moreover, the facilitation of glutamate release mediated by KAR requires the mobilization of intrasynaptosomal Ca(2+) stores and the formation of a Ca(2+)-calmodulin complex. We conclude that KARs present on presynaptic terminals in the neocortex mediate the facilitation of glutamate release through a mechanism involving an increase in cytosolic Ca(2+) to activate a Ca(2+)-calmodulin-AC/cAMP/PKA signaling cascade.

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

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.