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Results for “GluK2 Kainate Receptor”

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At least 19 recordsLinked to original sources
PubMed2002

External anions and cations distinguish between AMPA and kainate receptor gating mechanisms.

Experiments were designed to examine if ion-flow through alpha-amino-3-hydroxy-5-methyl-isoxazolepropionic acid (AMPA) or kainate receptors interferes with protein structures associated with the gating machinery. Gating was studied using ultra-fast drug perfusion of outside-out patches containing rat GluR-A or GluR6 subunits excised from transfected human embryonic kidney cells. Deactivation rates of GluR6 kainate receptors observed following brief L-glutamate (10 mM Glu, 1 ms) applications differed by two to threefold in high (405 mM symmetrical Na(+), tau(decay) = 2.7 ms at -100 mV) and low ionic strength (55 mM, tau(decay) = 1.1 ms) solutions. In comparison, GluR-A AMPA receptors were much less sensitive. Ion effects on GluR6 receptors did not reflect surface potential screening or ion-agonist competition at the agonist-binding site since deactivation rates were slower in high ionic strength solutions. Moreover, the apparent agonist affinity did not decrease with increasing ionic strength (e.g. 55 mM, EC(50) = 110 microM vs. 405 mM, EC(50) = 61 microM). GluR6 responses were strongly dependent on ions present on the external, but not the internal, side of the plasma membrane. Decay kinetics was regulated by the type of ion present suggesting that the chemical nature of the solution, not its ionic strength, governed channel behaviour. Both external anions and cations modulated the amplitude and decay kinetics of GluR6 responses in a concomitant manner. AMPA receptor responses recorded in identical ionic conditions did not exhibit this behaviour. These results identify a novel mechanism that distinguishes AMPA and kainate receptors. External ions regulate the gating machinery of kainate receptors through an allosteric mechanism that involves both anions and cations.

Animals↗
PubMed2001

Kainate receptors: knocking out plasticity.

There is increasing evidence that kainate receptors contribute to both postsynaptic and presynaptic signaling. Studies of knockout mice have played a pivotal role in defining the functions of kainate receptors, including a recent study that implicates kainate receptors in frequency-dependent facilitation and long-term potentiation of hippocampal mossy fiber synapses.

Animals↗
PubMed2002

Functional characterization of kainate receptors in the mouse nucleus accumbens.

Kainate receptors are abundantly expressed in the nucleus accumbens but their functional characterization and their role in synaptic transmission has not yet been investigated. Using patch-clamp recordings in mouse nucleus accumbens slices, we show the presence of functional kainate receptors activated by low concentrations of kainate (100-300 nM) in medium size neurons. These somatodendritic receptors are comprised of the GluR6 subunit, since they are absent in GluR6-deficient mice. Kainate receptors do not directly participate in glutamatergic synaptic transmission evoked by electrical stimulation of cortical afferent fibers in nucleus accumbens neurons. However, application of low concentrations of kainate inhibits cortico-accumbens synaptic transmission, by increasing synaptic failure rate and increasing variation coefficient, thus indicating a presynaptic site of action. Presynaptic kainate receptors are observed both in GluR6 and in GluR5-deficient mice, but are absent in mice devoid of both subunits. Hence, at variance with somatodendritic kainate receptors, presynaptic kainate receptors on cortical afferents are composed of both GluR5 and GluR6 kainate receptor subunits. These results indicate that different subtypes of kainate receptors, representing distinct pharmacological targets, should play important roles in the synaptic integration properties of nucleus accumbens neurons.

Animals↗
PubMed2006

Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate.

Ionotropic glutamate receptors perform diverse functions in the nervous system. As a result, multiple receptor subtypes have evolved with different kinetics, ion permeability, expression patterns, and regulation by second messengers. Kainate receptors show slower recovery from desensitization and have different affinities for agonists than AMPA receptors. Based on analysis of ligand binding domain crystal structures, we identified interdomain interactions in the agonist-bound state that are conserved in kainate receptors and absent in AMPA receptors. Mutations in GluR6 designed to disrupt these contacts reduced agonist apparent affinity, speeded up receptor deactivation and increased the rate of recovery from desensitization. Conversely, introduction of mutations in GluR2 that enabled additional interdomain interactions in the agonist-bound state increased agonist apparent affinity 15-fold, and slowed both deactivation and recovery from desensitization. We conclude that interdomain interactions have evolved as a distinct mechanism that contributes to the unique kinetic properties of AMPA and kainate receptors.

Animals↗
PubMed2005

Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity.

Little is known about the molecular mechanisms underlying differences in the ligand binding properties of AMPA, kainate, and NMDA subtype glutamate receptors. Crystal structures of the GluR5 and GluR6 kainate receptor ligand binding cores in complexes with glutamate, 2S,4R-4-methylglutamate, kainate, and quisqualate have now been solved. The structures reveal that the ligand binding cavities are 40% (GluR5) and 16% (GluR6) larger than for GluR2. The binding of AMPA- and GluR5-selective agonists to GluR6 is prevented by steric occlusion, which also interferes with the high-affinity binding of 2S,4R-4-methylglutamate to AMPA receptors. Strikingly, the extent of domain closure produced by the GluR6 partial agonist kainate is only 3 degrees less than for glutamate and 11 degrees greater than for the GluR2 kainate complex. This, together with extensive interdomain contacts between domains 1 and 2 of GluR5 and GluR6, absent from AMPA receptors, likely contributes to the high stability of GluR5 and GluR6 kainate complexes.

Amino Acid Sequence↗
PubMed1999

Reduced editing of low-affinity kainate receptor subunits in optic nerve glial cells.

We have analyzed the degree of editing of adult optic nerve mRNAs encoding the low-affinity kainate receptor subunits, GluR5 and GluR6, the two major constituents of native receptors in this family. To this end, we used reverse transcription (RT) followed by polymerase chain reaction (PCR), and subsequent cloning and sequencing of the amplified fragments. Our results revealed that the GluR5 subunit is unedited at the Q/R site of cismembrane domain 2 (M2), whereas the GluR6 subunit is edited to a low extent at this site. These findings are in contrast to those reported by others using mRNAs from the adult brain in which GluR5 and GluR6 are edited at the Q/R site of M2 to a larger extent. In addition, we found that the adenosine deaminases, DRADA, RED1 and RED2, which edit ionotropic glutamate receptors in the brain, are expressed in the adult optic nerve and in oligodendrocytes, the major cell type in this structure. It thus appears that editing of kainate receptors in optic nerve cells is not limited by the availability of editing enzymes but rather by other, as yet unidentified factors. Overall, reduced editing of kainate receptor subunits in glial cells may result in different functional responses of the native receptors present in these cells with respect to those in neurons.

Adenosine Deaminase↗
PubMed2006

Identification of an endoplasmic reticulum-retention motif in an intracellular loop of the kainate receptor subunit KA2.

Neuronal kainate receptors are typically heteromeric complexes composed of GluR5-7 and KA1-2 subunits. Although GluR5-7 can exist as functional homomeric channels, the KA subunits cannot. KA2 is widely expressed in the CNS, and KA2/GluR6 heteromers are the most prevalent subunit composition in brain. Previous work has identified endoplasmic reticulum (ER)-retention motifs in the C terminus of KA2, which prevent surface expression of KA2 homomers. However, we find that, when these motifs are mutated, only a small fraction of KA2 is surface expressed. We now identify an additional ER retention motif in the intracellular loop region of KA2, which, when mutated together with the C-terminal motifs, significantly increases the level of KA2 surface expression. However, electrophysiological analysis of surface-expressed KA2 homomers indicates that they do not form functional ion channels. In heterologous cells, a large fraction of KA2 remains intracellular even when the trafficking motifs are mutated or when GluR6 is coexpressed. Therefore, we analyzed the trafficking of endogenous KA2 in vivo. We find that native KA2 surface expression is dramatically reduced in GluR6 knock-out mice compared with wild-type mice. In contrast, KA2 trafficking was unaffected in the GluR5 knock-out. Thus, our study demonstrates that trafficking motifs in both the intracellular loop and C terminus regulate KA2 surface expression; however, in neurons, GluR6 oligomerization is required for egress of KA2 from the ER and transport to the cell surface. The combination of these mechanisms likely prevents surface expression of nonfunctional KA2 homomers and ensures a high level of GluR6/KA2 heteromeric kainate receptors.

Amino Acid Motifs↗
PubMed2001

The link between excitotoxic oligodendroglial death and demyelinating diseases.

Oligodendrocytes, the myelinating cells of CNS axons, are highly vulnerable to excitotoxic signals mediated by glutamate receptors of the AMPA and kainate classes. Receptors in these cells are commonly activated by glutamate that is released from axons and glial cells. In addition, oligodendrocytes contribute to the control of extracellular glutamate levels by means of their own transporters. However, acute and chronic alterations in glutamate homeostasis can result in overactivation of AMPA and kainate receptors and subsequent excitotoxic oligodendroglial death. Furthermore, demyelinating lesions caused by excitotoxins can be similar to those observed in multiple sclerosis. This, together with the effect of AMPA and kainate receptor antagonists in ameliorating the neurological score of animals with experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis), indicates that oligodendrocyte excitotoxicity could be involved in the pathogenesis of demyelinating disorders.

Animals↗
PubMed2005

The effect of three inhaled anesthetics in mice harboring mutations in the GluR6 (kainate) receptor gene.

Combinations of GluR5-GluR7, KA1, and KA2 subunits form kainate receptors, a subtype of excitatory ionotropic glutamate receptors. Isoflurane enhances the action of kainate receptors comprising GluR6 subunits expressed in oocytes. To test whether alterations of the GluR6 subunit gene affect the actions of inhaled anesthetics in vivo, we measured the minimum alveolar concentration of desflurane, isoflurane, and halothane in mice lacking the kainate receptor subunit GluR6 (GluR6 knockout mice) and mice with a dominant negative glutamine/arginine (Q/R) editing mutation in membrane domain 2 of the GluR6 receptor (GluR6 editing mutants), which increases the calcium permeability of kainate receptors containing GluR6Q. We also measured the capacity of isoflurane to interfere with Pavlovian fear conditioning to a tone and to context. Absence of the GluR6 subunit did not change the minimum alveolar concentration of isoflurane, desflurane, or halothane. Possibly, kainate receptors assembled from the remaining kainate receptor subunits compensate for the absent subunits and thereby produce a normal minimum alveolar concentration. A Q/R mutation that dominantly affects kainate receptors containing the GluR6 subunit in mice increased isoflurane minimum alveolar concentration (by 12%; P < 0.01), decreased desflurane minimum alveolar concentration (by 18%; P < 0.001), and did not change halothane minimum alveolar concentration (P = 0.25). These data may indicate that kainate receptors containing GluR6Q subunits differently modulate, directly or indirectly, the mechanism by which inhaled anesthetics cause immobility. The mutations of GluR6 that were studied did not affect the capacity of isoflurane to interfere with fear conditioning.

Anesthetics, Inhalation↗
PubMed1998

Characterization of neuronal migration disorders in neocortical structures: quantitative receptor autoradiography of ionotropic glutamate, GABA(A) and GABA(B) receptors.

Epileptiform activity was previously described [Luhmann et al. (1998) Eur. J. Neurosci., 10, 3085-3094] in the neocortex of the adult rat following freeze lesioning of the newborn neocortex. After a survival time of 3 months, a small area of dysplastic cortex surrounded by histologically normal (exofocal) neocortex was observed. The dysplastic cortex is characterized by the formation of a small sulcus and a three- to four-layered architecture. Two questions are addressed here: (i) is the hyperexcitability associated with changes in binding to major excitatory and inhibitory transmitter receptors in the dysplastic cortex?; and (ii) do such changes also occur in the exofocal cortex? Alterations in binding to glutamatergic N-methyl-D-aspartate (NMDA), (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate and GABA(A) and GABA(B) (gamma-aminobutyric acid) receptors are demonstrated with quantitative in vitro receptor autoradiography by using the ligands [3H]MK-801, [3H]AMPA, [3H]kainate, [3H]muscimol and [3H]baclofen, respectively. In the dysplastic cortex, the binding to NMDA, AMPA and kainate receptors is significantly increased, whereas the binding to GABA(A) and GABA(B) receptors is reduced. Exofocal areas of the lesioned hemisphere show an imbalance between excitatory and inhibitory receptor binding with an up-regulation of the binding to AMPA and kainate, and a down-regulation to GABA(A) receptors. The binding to GABA(B) and NMDA receptors is not significantly changed in the exofocal areas. The imbalance between excitatory and inhibitory receptors may cause the hyperexcitability, as previously found in the identical experimental model, and may also induce epileptiform activity in the human cortex with migration disorders.

Animals↗
PubMed2004

The kainate receptor subunit GluR6 mediates metabotropic regulation of the slow and medium AHP currents in mouse hippocampal neurones.

Kainate receptors (KARs) play an important role in synaptic physiology, plasticity and pathological phenomena such as epilepsy. However, the physiological implications for single cells and neuronal networks of the distinct expression patterns of KAR subunits are unknown. One intriguing effect of KAR activation is a long-term change to intrinsic neuronal excitability and neuronal firing patterns, such as single-spike and spike-burst firing. In this study, we describe the role of kainate receptor subunits in the metabotropic regulation of the slow and medium afterhyperpolarization (AHP) currents (I(sAHP), I(mAHP)). Using whole-cell patch-clamp recordings from CA3 pyramidal cells of wild-type (WT) and KAR knockout mice, we show that the kainate-induced decrease of I(sAHP) and I(mAHP) amplitude is protein-kinase-C-dependent and absent in GluR6(-/-) but not GluR5(-/-) pyramidal neurones. Our findings suggest that activation of GluR6-containing KARs modulates AHP amplitude, and influences the firing frequency of pyramidal neurones.

Action Potentials↗
PubMed2001

Dominance of the lurcher mutation in heteromeric kainate and AMPA receptor channels.

Homomeric glutamate receptor (GluR) channels become spontaneously active when the last alanine residue within the invariant SYTANLAAF-motif in the third membrane segment is substituted by threonine. The same mutation in the orphan GluRdelta2 channel is responsible for neurodegeneration in "Lurcher" (Lc) mice. Since most native GluRs are composed of different subunits, we investigated the effect of an Lc-mutated subunit in heteromeric kainate and AMPA receptors expressed in HEK293 cells. Kainate receptor KA2 subunits, either wild type or carrying the Lc mutation (KA2(Lc)), are retained inside the cell but are surface-expressed when assembled with GluR6 subunits. Importantly, KA2(Lc) dominates the gating of KA2(Lc)/GluR6(WT) channels, as revealed by spontaneous activation and by slowed desensitization and deactivation kinetics of ligand-activated whole-cell currents. Moreover, the AMPA receptor subunit GluR-B(Lc)(Q) which forms spontaneously active homomeric channels with rectifying current-voltage relationships, dominates the gating of heteromeric GluR-B(Lc)(Q)/GluR-A(R) channels. The spontaneous currents of these heteromeric AMPAR channels show linear current-voltage relationships, and the ligand-activated whole-cell currents display slower deactivation and desensitization kinetics than the respective wild-type channels. For heteromeric Lc-mutated kainate and AMPA receptors, the effects on kinetics were reduced relative to the homomeric Lc-mutated forms. Thus, an Lc-mutated subunit can potentially influence heteromeric channel function in vivo, and the severity of the phenotype will critically depend on the levels of homomeric GluR(Lc) and heteromeric GluR(Lc)/GluR(WT) channels.

Amino Acid Substitution↗
PubMed1998

A point mutation in the glutamate binding site blocks desensitization of AMPA receptors.

Desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors is thought to shape the synaptic response and act as a neuroprotective mechanism at central synapses, but the molecular mechanism underlying desensitization is poorly understood. We found that replacing the glutamate binding domain S1 of GluR3 (an AMPA receptor) with S1 of GluR6 (a kainate receptor) resulted in a fully active but completely nondesensitizing receptor. Smaller substitutions within S1 identified, besides two additional modulatory regions, a single exchange, L507Y, as is required and sufficient for the block of desensitization. This phenotype was specific for AMPA receptors and required an aromatic residue at this position. L507 lies between two residues (T504 and R509) that form part of the glutamate binding site. The physical proximity of these residues, which are involved in binding and gating, suggests they may form part of the link between these two events.

Binding Sites↗
PubMed1999

Evidence for the GluR6 gene associated with younger onset age of Huntington's disease.

Huntington's disease (HD) is attributed to a triplet CAG repeat mutation, and about half of the variation in onset age can be explained by the size of the repeat expansion. Recently, a TAA repeat polymorphism in close linkage to the kainate receptor, GluR6, was reported related to onset age in HD. We examined this polymorphism in 258 unrelated HD-affected persons (172 from a clinic sample and 86 from a postmortem series). This study confirms that the 155 allele is associated with younger onset age of HD and suggests that it is in linkage disequilibrium with a variant of the GluR6 gene or another gene in this region.

Adolescent↗
PubMed2004

Frequency and transmission of glutamate receptors GRIK2 and GRIK3 polymorphisms in patients with obsessive compulsive disorder.

Several lines of evidence suggest that obsessive compulsive disorder (OCD) could be the consequence of glutamatergic dysfunction. We performed a case-control study in 156 patients and 141 controls and the transmission disequilibrium test in 124 parent-offspring trios to search for association between OCD and two kainate receptors, GRIK2 and GRIK3. Using three single nucleotide polymorphisms (SNP) in GRIK2 and one in GRIK3, we found no evidence for association in case-control or family-based analyses. Only the GRIK2 SNP I867, recently associated with autism, was less transmitted than expected (p < 0.03), supporting a functional role for this variant. These findings suggest the need for further investigation of the role of GRIK2 in OCD.

Adolescent↗
PubMed2000

Kainate receptor subunit-positive gonadotropin-releasing hormone neurons express c-Fos during the steroid-induced luteinizing hormone surge in the female rat.

During the preovulatory and estradiol-progesterone-induced GnRH-LH surge, a subpopulation of GnRH neurons transiently expresses the transcription factor c-fos, which is a useful marker of cell activation. To further characterize this subpopulation of GnRH neurons, multiple immunohistochemical procedures were applied to visualize GnRH, c-Fos, KA2, GluR5, GluR6, and GluR7 receptor subunits during different phases of the estrogen-progesterone-induced LH surge. The results show that the LH surge begins at 1400 h and peaks at 1600 h before returning to baseline late in the evening. At 1400 h, about 50% of the GnRH neurons contained c-Fos, and this percentage remained high at 65% at 1600 and 2000 h. During the surge, 50% of the c-Fos-positive GnRH neurons contained KA2 receptor subunit protein at 1400 h, 65% of the c-Fos-positive GnRH neurons expressed the KA2 subunit at 1600 h, and 50% of the c-Fos-positive GnRH neurons expressed the KA2 subunit at 2000 h. As KA2 subunits require other kainate-preferring subunits to form functional receptor channels, we examined GnRH neurons for the presence of GluR5, GluR6, and GluR7 messenger RNA (mRNA) and protein. The results show that the KA2-containing GnRH neurons also contain GluR5 receptor subunit mRNA and protein, and that these GnRH neurons are c-Fos positive during the steroid-induced LH surge. To determine whether administration of kainate is sufficient to induce c-Fos in GnRH neurons, steroid-primed animals received iv injections of subseizure-inducing amounts of kainic acid and were processed for immunohistochemistry and in situ hybridization. The results show that kainic acid causes a significant increase in circulating LH; however, it does not induce c-Fos in GnRH neurons, nor does it cause an increase in GnRH mRNA. Together, the results suggest that a large subset of GnRH neurons expresses KA2 as well as GluR5 receptor subunits, which would allow the formation of functional glutamate receptor channels, and that this subset of GnRH neurons is activated during the steroid-induced LH surge.

Animals↗
PubMed2005

Altered behavioral responses to noxious stimuli and fear in glutamate receptor 5 (GluR5)- or GluR6-deficient mice.

Different kainate receptor (KAR) subtypes contribute to the regulation of both excitatory and inhibitory transmission. However, no study has reported a role for KAR subtypes in behavioral responses to persistent pain and fear memory. Here we show that responses to capsaicin or inflammatory pain were significantly reduced in mice lacking glutamate receptor 5 (GluR5) but not GluR6 subunits. In classic fear-memory tests, mice lacking GluR6 but not GluR5 showed a significant reduction in fear memory when measured 3, 7, or 14 d after training. Additionally, synaptic potentiation was significantly reduced in the lateral amygdala of GluR6 but not GluR5 knock-out mice. Our findings provide evidence that distinct KAR subtypes contribute to chemical/inflammatory pain and fear memory. Selectively targeting different KAR subtypes may provide a useful strategy for treating persistent pain and fear-related mental disorders.

Amygdala↗
PubMed1997

Characterization of RNA editing of the glutamate-receptor subunits GluR5 and GluR6 in granule cells during cerebellar development.

The non-NMDA class of ionotropic glutamate receptors are subject to RNA editing resulting in single amino acid changes within individual subunits that make up these oligomeric receptors. These amino acid changes result in significant alterations of important channel properties. Both edited and unedited versions of the kainate-receptor subunits GluR5 and GluR6 are present in brain, but whether this reflects the expression of both versions in individual types of neurons or differences in editing between different cell types is unclear. To characterize editing in a single identified type of central neuron, we have determined the extent to which GluR5 and GluR6 mRNAs are edited in acutely isolated cerebellar granule cells. RT-PCR analysis revealed that editing at each site in GluR5 and GluR6 increased during early postnatal development. The Q/R site was predominantly unedited in GluR5, whereas GluR6 was mostly edited. The Q/R and Y/C sites of GluR6 were edited to similar extents, whereas a smaller percentage of transcripts were edited at the I/V site. The expression of two double-stranded RNA adenosine deaminases implicated in GluR editing (DRADA and RED1) increased in granule cells between postnatal days 1 and 15. Finally, cerebellar granule cells express a previously unreported variant of RED1 which appears to arise from developmentally regulated alternative splicing.

Adenosine Deaminase↗