PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses

Suzuki, Etsuko; Kamiya, Haruyuki

doi:10.1016/j.neures.2015.12.011

Cited by 8 publications

(7 citation statements)

References 33 publications

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“…Several synapse-associated proteins, especially PSD95 protein, were identified as interacting proteins for the kainate receptors [ 45 , 46 , 47 ]. For example, co-immunoprecipitations using rat brain extracts showed that GRIK2 and GRIK5 proteins were associated with the PSD95 protein [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Ultrarare Loss-of-Function Mutations in the Genes Encoding the Ionotropic Glutamate Receptors of Kainate Subtypes Associated with Schizophrenia Disrupt the Interaction with PSD95

Hsu

et al. 2022

JPM

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Schizophrenia is a complex mental disorder with a genetic component. The GRIK gene family encodes ionotropic glutamate receptors of the kainate subtype, which are considered candidate genes for schizophrenia. We screened for rare and pathogenic mutations in the protein-coding sequences of the GRIK gene family in 516 unrelated patients with schizophrenia using the ion semiconductor sequencing method. We identified 44 protein-altered variants, and in silico analysis indicated that 36 of these mutations were rare and damaging or pathological based on putative protein function. Notably, we identified four truncating mutations, including two frameshift deletion mutations (GRIK1p.Phe24fs and GRIK1p.Thr882fs) and two nonsense mutations (GRIK2p.Arg300Ter and GRIK4p.Gln342Ter) in four unrelated patients with schizophrenia. They exhibited minor allele frequencies of less than 0.01% and were absent in 1517 healthy controls from Taiwan Biobank. Functional analysis identified these four truncating mutants as loss-of-function (LoF) mutants in HEK-293 cells. We also showed that three mutations (GRIK1p.Phe24fs, GRIK1p.Thr882fs, and GRIK2p.Arg300Ter) weakened the interaction with the PSD95 protein. The results suggest that the GRIK gene family harbors ultrarare LoF mutations in some patients with schizophrenia. The identification of proteins that interact with the kainate receptors will be essential to determine kainate receptor-mediated signaling in the brain.

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Section: Discussionmentioning

confidence: 99%

Ultrarare Loss-of-Function Mutations in the Genes Encoding the Ionotropic Glutamate Receptors of Kainate Subtypes Associated with Schizophrenia Disrupt the Interaction with PSD95

Hsu

et al. 2022

JPM

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“…What constitutes a KAR synaptic slot remains an open question. Possibilities include PDZ-domain-containing proteins such as PSD95, PICK or GRIP 14 15 37 54 , although re-expression of a mutated GluK2a subunit lacking the four last amino acids responsible for the interaction with PDZ domain proteins did not affect KAR-EPSCs. In contrast, removal of the last 14 amino acids of GluK2a strongly had an impact on the amplitude of KAR-EPSCs.…”

Section: Discussionmentioning

confidence: 99%

Molecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells

et al. 2016

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Distinct subtypes of ionotropic glutamate receptors can segregate to specific synaptic inputs in a given neuron. Using functional mapping by focal glutamate uncaging in CA3 pyramidal cells (PCs), we observe that kainate receptors (KARs) are strictly confined to the postsynaptic elements of mossy fibre (mf) synapses and excluded from other glutamatergic inputs and from extrasynaptic compartments. By molecular replacement in organotypic slices from GluK2 knockout mice, we show that the faithful rescue of KAR segregation at mf-CA3 synapses critically depends on the amount of GluK2a cDNA transfected and on a sequence in the GluK2a C-terminal domain responsible for interaction with N-cadherin. Targeted deletion of N-cadherin in CA3 PCs greatly reduces KAR content in thorny excrescences and KAR-EPSCs at mf-CA3 synapses. Hence, multiple mechanisms combine to confine KARs at mf-CA3 synapses, including a stringent control of the amount of GluK2 subunit in CA3 PCs and the recruitment/stabilization of KARs by N-cadherins.

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“…However, PSD-95 not only mediates aforesaid complexes, but also fulfils crucial roles in maintaining and regulating the three-dimensional molecular structures at the postsynaptic density of glutamatergic synapses (Chen et al, 2011). In particular, PSD-95 knockout mice were associated with reduced hippocampal KAR contents (Suzuki and Kamiya, 2016), indicating that IR drug-mediated reductions of PSD-95 may also be neuroprotective against KA toxicity through subsequent decreases of synaptic KAR contents.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice

Keller

Garcı́a-Sevilla

2016

J Psychopharmacol

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This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.

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PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses

Cited by 8 publications

References 33 publications

Ultrarare Loss-of-Function Mutations in the Genes Encoding the Ionotropic Glutamate Receptors of Kainate Subtypes Associated with Schizophrenia Disrupt the Interaction with PSD95

Ultrarare Loss-of-Function Mutations in the Genes Encoding the Ionotropic Glutamate Receptors of Kainate Subtypes Associated with Schizophrenia Disrupt the Interaction with PSD95

Molecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice

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