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Graham L. Collingridge - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 Kainate Receptor antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Andrew Alt, David Bleakman, Jody L Knauss, Olli T. Pentikäinen, Carla Glasser, Mark L. Mayer, Graham L. CollingridgeAbstract:Some N3-substituted analogues of willardiine such as 11 and 13 are selective Kainate Receptor antagonists. In an attempt to improve the potency and selectivity for Kainate Receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing Kainate Receptors (KB values of 7 ± 1 and 5 ± 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 μM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.
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functional maturation of ca1 synapses involves activity dependent loss of tonic Kainate Receptor mediated inhibition of glutamate release
Neuron, 2006Co-Authors: Sari E. Lauri, John T.r. Isaac, Graham L. Collingridge, Aino Vesikansa, Mikael Segerstrale, Tomi TairaAbstract:Early in development, excitatory synapses transmit with low efficacy, one mechanism for which is a low probability of transmitter release (Pr). However, little is known about the developmental mechanisms that control activity-dependent maturation of the presynaptic release. Here, we show that during early development, transmission at CA3-CA1 synapses is regulated by a high-affinity, G protein-dependent Kainate Receptor (KAR), which is endogenously activated by ambient glutamate. By tonically depressing glutamate release, this mechanism sets the dynamic properties of neonatal inputs to favor transmission during high frequency bursts of activity, typical for developing neuronal networks. In response to induction of LTP, the tonic activation of KAR is rapidly down regulated, causing an increase in Pr and profoundly changing the dynamic properties of transmission. Early development of the glutamatergic connectivity thus involves an activity-dependent loss of presynaptic KAR function producing maturation in the mode of excitatory transmission from CA3 to CA1.
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structure activity relationship studies on n3 substituted willardiine derivatives acting as ampa or Kainate Receptor antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Jody L Knauss, David Bleakman, Graham L. CollingridgeAbstract:N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and Kainate Receptor antagonists. In an attempt to improve the potency and selectivity of these AMPA and Kainate Receptor antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing Kainate Receptors (KD 0.105 ± 0.007 μM vs Kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5-fluorowillardiine on native AMPA Receptors). On recombinant human GLUK5, GLUK5/GLUK6, and GLUK5/GLUK2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 Kainate Receptors or homomeric GLUA1-4 AMPA Receptors (IC50 values > 100 μM). Thus, 43 is a po...
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a role for ca2 stores in Kainate Receptor dependent synaptic facilitation and ltp at mossy fiber synapses in the hippocampus
Neuron, 2003Co-Authors: David Bleakman, Sari E. Lauri, Zuner A. Bortolotto, Paul L. Ornstein, David Lodge, John T.r. Isaac, Graham L. Collingridge, Robert NisticòAbstract:Compared with NMDA Receptor-dependent LTP, much less is known about the mechanism of induction of NMDA Receptor-independent LTP; the most extensively studied form of which is mossy fiber LTP in the hippocampus. In the present study we show that Ca2+-induced Ca2+ release from intracellular stores is involved in the induction of mossy fiber LTP. This release also contributes to the Kainate Receptor-dependent component of the pronounced synaptic facilitation that occurs during high-frequency stimulation. We also present evidence that the trigger for this Ca2+ release is Ca2+ permeation through Kainate Receptors. However, these novel synaptic mechanisms can be bypassed when the Ca2+ concentration is raised (from 2 to 4 mM), via a compensatory involvement of L-type Ca2+ channels. These findings suggest that presynaptic Kainate Receptors at mossy fiber synapses can initiate a cascade involving Ca2+ release from intracellular stores that is important in both short-term and long-term plasticity.
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A critical role of a facilitatory presynaptic Kainate Receptor in mossy fiber LTP.
Neuron, 2001Co-Authors: Sari E. Lauri, David Bleakman, Zuner A. Bortolotto, Paul L. Ornstein, David Lodge, John T.r. Isaac, Graham L. CollingridgeAbstract:The mechanisms involved in mossy fiber LTP in the hippocampus are not well established. In the present study, we show that the Kainate Receptor antagonist LY382884 (10 μM) is selective for presynaptic Kainate Receptors in the CA3 region of the hippocampus. At a concentration at which it blocks mossy fiber LTP, LY382884 selectively blocks the synaptic activation of a presynaptic Kainate Receptor that facilitates AMPA Receptor-mediated synaptic transmission. Following the induction of mossy fiber LTP, there is a complete loss of the presynaptic Kainate Receptor-mediated facilitation of synaptic transmission. These results identify a central role for the presynaptic Kainate Receptor in the induction of mossy fiber LTP. In addition, these results suggest that the pathway by which Kainate Receptors facilitate glutamate release is utilized for the expression of mossy fiber LTP.
Stephen F Heinemann - One of the best experts on this subject based on the ideXlab platform.
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structure of the Kainate Receptor subunit glur6 agonist binding domain complexed with domoic acid
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Max H Nanao, Stephen F Heinemann, Tim Green, Yael Sternbach, Senyon ChoeAbstract:We report the crystal structure of the glycosylated ligand-binding (S1S2) domain of the Kainate Receptor subunit GluR6, in complex with the agonist domoate. The structure shows the expected overall homology with AMPA and NMDA Receptor subunit structures but reveals an unexpected binding mode for the side chain of domoate, in which contact is made to the larger lobe only (lobe I). In common with the AMPA Receptor subunit GluR2, the GluR6 S1S2 domain associates as a dimer, with many of the interdimer contacts being conserved. Subtle differences in these contacts provide a structural explanation for why GluR2 L483Y and GluR3 L507Y are nondesensitizing, but GluR6, which has a tyrosine at that site, is not. The structure incorporates native glycosylation, which has not previously been described for ionotropic glutamate Receptors. The position of the sugars near the subunit interface rules out their direct involvement in subunit association but leaves open the possibility of indirect modulation. Finally, we observed several tetrameric assemblies that satisfy topological constraints with respect to connection to the Receptor pore, and which are therefore candidates for the native quaternary structure.
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the Kainate Receptor subunit glur6 mediates metabotropic regulation of the slow and medium ahp currents in mouse hippocampal neurones
The Journal of Physiology, 2005Co-Authors: Andre Fisahn, Stephen F Heinemann, Chris J McbainAbstract: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 (IsAHP, ImAHP). 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 IsAHP and ImAHP 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.
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Distribution of Kainate Receptor subunits at hippocampal mossy fiber synapses.
The Journal of Neuroscience, 2003Co-Authors: Melanie Darstein, Geoffrey T Swanson, Ronald S. Petralia, Robert J. Wenthold, Stephen F HeinemannAbstract:Kainate Receptors function as mediators of postsynaptic currents and as presynaptic modulators of synaptic transmission at mossy fiber synapses. Despite intense research into the physiological properties of mossy fiber Kainate Receptors, their subunit composition in the presynaptic and postsynaptic compartments is unclear. Here we describe the distribution of Kainate Receptor subunits in mossy fiber synapses using subunit-selective antibodies and knock-out mice. We provide morphological evidence for the presynaptic localization of KA1 and KA2 Receptor subunits at mossy fiber synapses. Immunogold staining for KA1 and KA2 was commonly seen at synaptic contacts and in vesicular structures. Postsynaptic labeling in dendritic spines was also observed. Although KA1 predominantly showed presynaptic localization, KA2 was concentrated to a greater degree on postsynaptic membranes. Both subunits coimmunoprecipitated from hippocampal membrane extracts with GluR6 but not GluR7 subunits. These results demonstrate that KA1 and KA2 subunits are localized presynaptically and postsynaptically at mossy fiber synapses where they most likely coassemble with GluR6 subunits to form functional heteromeric Kainate Receptor complexes.
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loss of Kainate Receptor mediated heterosynaptic facilitation of mossy fiber synapses in ka2 mice
The Journal of Neuroscience, 2003Co-Authors: Anis Contractor, Cornelia Maron, Geoffrey T Swanson, Melanie Darstein, Andreas W Sailer, Stephen F HeinemannAbstract:Multimeric assemblies of Kainate (KA) Receptor subunits form glutamate-gated ion channels that mediate EPSCs and function as presynaptic modulators of neurotransmitter release at some central synapses. The KA2 subunit is a likely constituent of many neuronal Kainate Receptors, because it is widely expressed in most neurons in the CNS. We have studied the effect of genetic ablation of this Receptor subunit on synaptic transmission at the mossy-fiber–CA3 pyramidal cell synapse in hippocampal slices, where Kainate Receptors are localized to both presynaptic and postsynaptic sites. We found that both postsynaptic and presynaptic mossy-fiber Kainate Receptor function is altered in neurons from KA2−/− mice. The presynaptic facilitatory autoReceptor, which modulates glutamate release from mossy-fiber terminals, had a reduced affinity for exogenous agonists and synaptic glutamate. Although presynaptic facilitation attributable to homosynaptic glutamate release was normal at mossy-fiber synapses in KA2−/− neurons, heterosynaptic Kainate Receptor-mediated facilitation resulting from the spillover of glutamate from CA3 collateral synapses was absent. Consistent with a decrease in glutamate affinity of the Receptor, the half-decay of the postsynaptic Kainate-mediated EPSC was shorter in the knock-out mice. These results identify the KA2 subunit as a determinant of Kainate Receptor function at presynaptic and postsynaptic mossy-fiber Kainate Receptors.
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identification of the Kainate Receptor subunits underlying modulation of excitatory synaptic transmission in the ca3 region of the hippocampus
The Journal of Neuroscience, 2000Co-Authors: Anis Contractor, Geoffrey T Swanson, Andreas W Sailer, Stephen Ogorman, Stephen F HeinemannAbstract:To understand the physiological role of Kainate Receptors and their participation in seizure induction in animal models of epilepsy, it will be necessary to develop a comprehensive description of their action in the CA3 region of the hippocampus. Activation of presynaptic Kainate Receptors depresses excitatory synaptic transmission at mossy fiber and associational-commissural inputs to CA3 pyramidal neurons (Vignes et al., 1998; Bortolotto et al., 1999; Kamiya and Ozawa, 2000). In this study, we use gene-targeted mice lacking glutamate Receptor 5 (GluR5) or GluR6 Kainate Receptor subunits to identify the Receptor subunits that comprise the Kainate Receptors responsible for presynaptic modulation of CA3 transmission. We found that bath application of Kainate (3 microm) profoundly reduced EPSCs at mossy fiber and collateral synapses in neurons from wild-type and GluR5(-/-) mice but had no effect on EPSCs in neurons from GluR6(-/-) mice. These results therefore contrast with previous studies that supported a role for GluR5-containing Receptors at mossy fiber and associational-commissural synapses (Vignes et al., 1998; Bortolotto et al., 1999). Surprisingly, at perforant path synapses Kainate Receptor activation enhanced transmission; this potentiation was abolished in both GluR5 and GluR6 knock-out mice. Kainate Receptors thus play multiple and complex roles to modulate excitatory synaptic transmission in the CA3 region of the hippocampus.
David Bleakman - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and pharmacological characterization of N3-substituted willardiine derivatives: role of the substituent at the 5-position of the uracil ring in the development of highly potent and selective GLUK5 Kainate Receptor antagonists.
Journal of medicinal chemistry, 2007Co-Authors: Andrew Alt, David Bleakman, Jody L Knauss, Olli T. Pentikäinen, Carla Glasser, Mark L. Mayer, Graham L. CollingridgeAbstract:Some N3-substituted analogues of willardiine such as 11 and 13 are selective Kainate Receptor antagonists. In an attempt to improve the potency and selectivity for Kainate Receptors, a range of analogues of 11 and 13 were synthesized with 5-substituents on the uracil ring. An X-ray crystal structure of the 5-methyl analogue of 13 bound to GLUK5 revealed that there was allowed volume around the 4- and 5-positions of the thiophene ring, and therefore the 4,5-dibromo and 5-phenyl (67) analogues were synthesized. Compound 67 (ACET) demonstrated low nanomolar antagonist potency on native and recombinant GLUK5-containing Kainate Receptors (KB values of 7 ± 1 and 5 ± 1 nM for antagonism of recombinant human GLUK5 and GLUK5/GLUK2, respectively) but displayed IC50 values >100 μM for antagonism of GLUA2, GLUK6, or GLUK6/GLUK2.
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structure activity relationship studies on n3 substituted willardiine derivatives acting as ampa or Kainate Receptor antagonists
Journal of Medicinal Chemistry, 2006Co-Authors: Jody L Knauss, David Bleakman, Graham L. CollingridgeAbstract:N3-Substitution of the uracil ring of willardiine with a variety of carboxyalkyl or carboxybenzyl substituents produces AMPA and Kainate Receptor antagonists. In an attempt to improve the potency and selectivity of these AMPA and Kainate Receptor antagonists a series of analogues with different terminal acidic groups and interacidic group spacers was synthesized and pharmacologically characterized. (S)-1-(2-Amino-2-carboxyethyl)-3-(2-carboxythiophene-3-ylmethyl)pyrimidine-2,4-dione (43, UBP304) demonstrated high potency and selectivity toward native GLUK5-containing Kainate Receptors (KD 0.105 ± 0.007 μM vs Kainate on native GLUK5; KD 71.4 ± 8.3 μM vs (S)-5-fluorowillardiine on native AMPA Receptors). On recombinant human GLUK5, GLUK5/GLUK6, and GLUK5/GLUK2, KB values of 0.12 ± 0.03, 0.12 ± 0.01, and 0.18 ± 0.02 μM, respectively, were obtained for 43. However, 43 displayed no activity on homomeric GLUK6 or GLUK7 Kainate Receptors or homomeric GLUA1-4 AMPA Receptors (IC50 values > 100 μM). Thus, 43 is a po...
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a role for ca2 stores in Kainate Receptor dependent synaptic facilitation and ltp at mossy fiber synapses in the hippocampus
Neuron, 2003Co-Authors: David Bleakman, Sari E. Lauri, Zuner A. Bortolotto, Paul L. Ornstein, David Lodge, John T.r. Isaac, Graham L. Collingridge, Robert NisticòAbstract:Compared with NMDA Receptor-dependent LTP, much less is known about the mechanism of induction of NMDA Receptor-independent LTP; the most extensively studied form of which is mossy fiber LTP in the hippocampus. In the present study we show that Ca2+-induced Ca2+ release from intracellular stores is involved in the induction of mossy fiber LTP. This release also contributes to the Kainate Receptor-dependent component of the pronounced synaptic facilitation that occurs during high-frequency stimulation. We also present evidence that the trigger for this Ca2+ release is Ca2+ permeation through Kainate Receptors. However, these novel synaptic mechanisms can be bypassed when the Ca2+ concentration is raised (from 2 to 4 mM), via a compensatory involvement of L-type Ca2+ channels. These findings suggest that presynaptic Kainate Receptors at mossy fiber synapses can initiate a cascade involving Ca2+ release from intracellular stores that is important in both short-term and long-term plasticity.
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Kainate Receptor agonists antagonists and allosteric modulators
Current Pharmaceutical Design, 2002Co-Authors: David Bleakman, M R Gates, Annmarie Ogden, M MackowiakAbstract:Interest in Kainate Receptors has increased over the past few years. Our understanding of their physiology and pharmacology has improved markedly since their original cloning and expression in the early 1990s. For example, agonist profiles at recombinant Kainate Receptors have been used to identify and distinguish Kainate Receptors in neurons. Furthermore, the development of selective antagonists for Kainate Receptor subtypes has increased our understanding of the functional roles of Kainate Receptors in neurons and synaptic transmission. In this review we described the activity of agonists and antagonists at Kainate Receptors and their selectivity profiles at NMDA and non-NMDA Receptors.
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A critical role of a facilitatory presynaptic Kainate Receptor in mossy fiber LTP.
Neuron, 2001Co-Authors: Sari E. Lauri, David Bleakman, Zuner A. Bortolotto, Paul L. Ornstein, David Lodge, John T.r. Isaac, Graham L. CollingridgeAbstract:The mechanisms involved in mossy fiber LTP in the hippocampus are not well established. In the present study, we show that the Kainate Receptor antagonist LY382884 (10 μM) is selective for presynaptic Kainate Receptors in the CA3 region of the hippocampus. At a concentration at which it blocks mossy fiber LTP, LY382884 selectively blocks the synaptic activation of a presynaptic Kainate Receptor that facilitates AMPA Receptor-mediated synaptic transmission. Following the induction of mossy fiber LTP, there is a complete loss of the presynaptic Kainate Receptor-mediated facilitation of synaptic transmission. These results identify a central role for the presynaptic Kainate Receptor in the induction of mossy fiber LTP. In addition, these results suggest that the pathway by which Kainate Receptors facilitate glutamate release is utilized for the expression of mossy fiber LTP.
Sari E. Lauri - One of the best experts on this subject based on the ideXlab platform.
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functional maturation of ca1 synapses involves activity dependent loss of tonic Kainate Receptor mediated inhibition of glutamate release
Neuron, 2006Co-Authors: Sari E. Lauri, John T.r. Isaac, Graham L. Collingridge, Aino Vesikansa, Mikael Segerstrale, Tomi TairaAbstract:Early in development, excitatory synapses transmit with low efficacy, one mechanism for which is a low probability of transmitter release (Pr). However, little is known about the developmental mechanisms that control activity-dependent maturation of the presynaptic release. Here, we show that during early development, transmission at CA3-CA1 synapses is regulated by a high-affinity, G protein-dependent Kainate Receptor (KAR), which is endogenously activated by ambient glutamate. By tonically depressing glutamate release, this mechanism sets the dynamic properties of neonatal inputs to favor transmission during high frequency bursts of activity, typical for developing neuronal networks. In response to induction of LTP, the tonic activation of KAR is rapidly down regulated, causing an increase in Pr and profoundly changing the dynamic properties of transmission. Early development of the glutamatergic connectivity thus involves an activity-dependent loss of presynaptic KAR function producing maturation in the mode of excitatory transmission from CA3 to CA1.
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a role for ca2 stores in Kainate Receptor dependent synaptic facilitation and ltp at mossy fiber synapses in the hippocampus
Neuron, 2003Co-Authors: David Bleakman, Sari E. Lauri, Zuner A. Bortolotto, Paul L. Ornstein, David Lodge, John T.r. Isaac, Graham L. Collingridge, Robert NisticòAbstract:Compared with NMDA Receptor-dependent LTP, much less is known about the mechanism of induction of NMDA Receptor-independent LTP; the most extensively studied form of which is mossy fiber LTP in the hippocampus. In the present study we show that Ca2+-induced Ca2+ release from intracellular stores is involved in the induction of mossy fiber LTP. This release also contributes to the Kainate Receptor-dependent component of the pronounced synaptic facilitation that occurs during high-frequency stimulation. We also present evidence that the trigger for this Ca2+ release is Ca2+ permeation through Kainate Receptors. However, these novel synaptic mechanisms can be bypassed when the Ca2+ concentration is raised (from 2 to 4 mM), via a compensatory involvement of L-type Ca2+ channels. These findings suggest that presynaptic Kainate Receptors at mossy fiber synapses can initiate a cascade involving Ca2+ release from intracellular stores that is important in both short-term and long-term plasticity.
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A critical role of a facilitatory presynaptic Kainate Receptor in mossy fiber LTP.
Neuron, 2001Co-Authors: Sari E. Lauri, David Bleakman, Zuner A. Bortolotto, Paul L. Ornstein, David Lodge, John T.r. Isaac, Graham L. CollingridgeAbstract:The mechanisms involved in mossy fiber LTP in the hippocampus are not well established. In the present study, we show that the Kainate Receptor antagonist LY382884 (10 μM) is selective for presynaptic Kainate Receptors in the CA3 region of the hippocampus. At a concentration at which it blocks mossy fiber LTP, LY382884 selectively blocks the synaptic activation of a presynaptic Kainate Receptor that facilitates AMPA Receptor-mediated synaptic transmission. Following the induction of mossy fiber LTP, there is a complete loss of the presynaptic Kainate Receptor-mediated facilitation of synaptic transmission. These results identify a central role for the presynaptic Kainate Receptor in the induction of mossy fiber LTP. In addition, these results suggest that the pathway by which Kainate Receptors facilitate glutamate release is utilized for the expression of mossy fiber LTP.
Geoffrey T Swanson - One of the best experts on this subject based on the ideXlab platform.
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complete disruption of the Kainate Receptor gene family results in corticostriatal dysfunction in mice
Cell Reports, 2017Co-Authors: John Marshall, Geoffrey T Swanson, Herman B Fernandes, Bryan A Copits, Toshihiro Nomura, Daniele Procissi, Susumu Mori, Lei Wang, Yongling Zhu, Anis ContractorAbstract:Summary Kainate Receptors are members of the glutamate Receptor family that regulate synaptic function in the brain. They modulate synaptic transmission and the excitability of neurons; however, their contributions to neural circuits that underlie behavior are unclear. To understand the net impact of Kainate Receptor signaling, we generated knockout mice in which all five Kainate Receptor subunits were ablated (5ko). These mice displayed compulsive and perseverative behaviors, including over-grooming, as well as motor problems, indicative of alterations in striatal circuits. There were deficits in corticostriatal input to spiny projection neurons (SPNs) in the dorsal striatum and correlated reductions in spine density. The behavioral alterations were not present in mice only lacking the primary Receptor subunit expressed in adult striatum (GluK2 KO), suggesting that signaling through multiple Receptor types is required for proper striatal function. This demonstrates that alterations in striatal function dominate the behavioral phenotype in mice without Kainate Receptors.
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dancing partners at the synapse auxiliary subunits that shape Kainate Receptor function
Nature Reviews Neuroscience, 2012Co-Authors: Bryan A Copits, Geoffrey T SwansonAbstract:Kainate Receptors are a family of ionotropic glutamate Receptors whose physiological roles differ from those of other subtypes of glutamate Receptors in that they predominantly serve as modulators, rather than mediators, of synaptic transmission. Neuronal Kainate Receptors exhibit unusually slow kinetic properties that have been difficult to reconcile with the behaviour of recombinant Kainate Receptors. Recently, however, the neuropilin and tolloid-like 1 (NETO1) and NETO2 proteins were identified as auxiliary Kainate Receptor subunits that shape both the biophysical properties and synaptic localization of these Receptors.
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high affinity Kainate Receptor subunits are necessary for ionotropic but not metabotropic signaling
Neuron, 2009Co-Authors: Herman B Fernandes, Geoffrey T Swanson, Ronald S. Petralia, Justin S Catches, Bryan A Copits, Theron A Russell, Anis ContractorAbstract:Summary Kainate Receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five Receptor subunits, as they do not form homomeric Receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic Kainate Receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic Kainate Receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining Kainate Receptors. Despite this, Kainate Receptor-mediated inhibition of the slow afterhyperpolarization current (I sAHP ), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic Kainate Receptor function and further demonstrate that Kainate Receptor participation in metabotropic signaling pathways does not require their classic role as ion channels.
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Distribution of Kainate Receptor subunits at hippocampal mossy fiber synapses.
The Journal of Neuroscience, 2003Co-Authors: Melanie Darstein, Geoffrey T Swanson, Ronald S. Petralia, Robert J. Wenthold, Stephen F HeinemannAbstract:Kainate Receptors function as mediators of postsynaptic currents and as presynaptic modulators of synaptic transmission at mossy fiber synapses. Despite intense research into the physiological properties of mossy fiber Kainate Receptors, their subunit composition in the presynaptic and postsynaptic compartments is unclear. Here we describe the distribution of Kainate Receptor subunits in mossy fiber synapses using subunit-selective antibodies and knock-out mice. We provide morphological evidence for the presynaptic localization of KA1 and KA2 Receptor subunits at mossy fiber synapses. Immunogold staining for KA1 and KA2 was commonly seen at synaptic contacts and in vesicular structures. Postsynaptic labeling in dendritic spines was also observed. Although KA1 predominantly showed presynaptic localization, KA2 was concentrated to a greater degree on postsynaptic membranes. Both subunits coimmunoprecipitated from hippocampal membrane extracts with GluR6 but not GluR7 subunits. These results demonstrate that KA1 and KA2 subunits are localized presynaptically and postsynaptically at mossy fiber synapses where they most likely coassemble with GluR6 subunits to form functional heteromeric Kainate Receptor complexes.
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multiple trafficking signals regulate Kainate Receptor ka2 subunit surface expression
The Journal of Neuroscience, 2003Co-Authors: Zhao Ren, Geoffrey T Swanson, Elizabeth P Garcia, Nathan J Riley, James M Sanders, John MarshallAbstract:The Kainate Receptor subunit KA2 does not form functional homomeric channels despite its structural similarity to the functional glutamate Receptor 5-7subunits and high agonist binding affinity in in vitro assays. In this study, we first demonstrate that homomeric KA2 Receptors fail to reach the plasma membrane and then identify the molecular mechanisms preventing surface expression. Specifically, we show that KA2 subunits form homooligomeric Receptors that are confined to the endoplasmic reticulum (ER). We then demonstrate that, in both heterologous expression systems and primary neurons, the intracellular retention of KA2 is not caused by subunit misfolding but, rather, is mediated through discrete protein trafficking signals, including an arginine-rich ER retention/retrieval motif and a di-leucine endocytic sequence in the C terminus of the KA2 subunit. Disruption of these motifs results in ER exit and surface expression of KA2 homomeric Receptors that remain nonfunctional. Furthermore, our data suggest that the ER retention/retrieval signal in KA2 is sterically shielded during heteromeric assembly, allowing delivery of functional heteromeric Receptors to the plasma membrane. Taken together, our results illustrate novel regulatory mechanisms that control the intracellular trafficking and surface expression of Kainate Receptors.