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.

Cerebellar Kainate Receptor-Mediated Facilitation of Glutamate Release Requires Ca-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.

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.

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.

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.

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.

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).

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.

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 Gβγ subunit to a decrease in Ca(2+) channel function.

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.

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.

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.

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.

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).

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.

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.

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.

Attenuation of phospholipid signaling provides a novel mechanism for the action of valproic acid.

Valproic acid (VPA) is used to treat epilepsy and bipolar disorder and to prevent migraine. It is also undergoing trials for cancer therapy. However, the biochemical and molecular biological actions of VPA are poorly understood.

Unexpected inhibitory regulation of glutamate release from rat cerebrocortical nerve terminals by presynaptic 5-hydroxytryptamine-2A receptors.

Presynaptic 5-HT(2A) receptor modulation of glutamate release from rat cerebrocortical nerve terminals (synaptosomes) was investigated by using the 5-HT(2A/2C) receptor agonist (+/-)-1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI). DOI potently inhibited 4-aminopyridine (4AP)-evoked glutamate release. Involvement of presynaptic 5-HT(2A) receptors in this modulation of 4AP-evoked release was confirmed by blockade of the DOI-mediated inhibition by the 5-HT(2A) receptor antagonist ketanserin but not by the 5-HT(2C) receptor antagonist RS102221.

Kainate receptor-mediated inhibition of glutamate release involves protein kinase A in the mouse hippocampus.

The mechanisms involved in the inhibition of glutamate release mediated by the activation of presynaptic kainate receptors (KARs) at the hippocampal mossy fiber-CA3 synapse are not well understood. We have observed a long-lasting inhibition of CA3 evoked excitatory postsynaptic currents (eEPSCs) after a brief application of kainate (KA) at concentrations ranging from 0.3 to 10 muM.

Presynaptic kainate receptor facilitation of glutamate release involves protein kinase A in the rat hippocampus.

We have explored the mechanisms involved in the facilitation of glutamate release mediated by the activation of kainate receptors in the rat hippocampus using isolated nerve terminal (synaptosome) and slice preparations. In hippocampal nerve terminals, kainate (KA) produced an increase of glutamate release at concentrations of agonist ranging from 10 to 1000 microm. In hippocampal slices, KA at low nanomolar concentrations (20-50 nm) also produced an increase of evoked excitatory postsynaptic currents (eEPSCs) at mossy fibre-CA3 synapses.

Noncompetitive metabotropic glutamate5 receptor antagonist (E)-2-methyl-6-styryl-pyridine (SIB1893) depresses glutamate release through inhibition of voltage-dependent Ca2+ entry in rat cerebrocortical nerve terminals (synaptosomes).

The effect of (E)-2-methyl-6-styryl-pyridine (SIB1893), a selective metabotropic glutamate (subtype 5) receptor (mGlu(5)R) antagonist, on glutamate release from isolated nerve terminals (synaptosomes) was examined. SIB1893 caused a potent inhibition of the Ca(2+)-dependent release of glutamate evoked by 4-aminopyridine (4AP). That the implied mGlu(5)R-mediated modulation was contingent on diacylglycerol stimulation of protein kinase C (PKC) was indicated by PKC activator phorbol dibutyrate and PKC inhibitor Ro 32-0432 (bisindolylmaleimide XI), respectively, superceding or suppressing the inhibitory effect of SIB1893.

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.