Orphan Glutamate Receptor δ1 Subunit Required for High-Frequency Hearing

Gao, Jiangang; Maison, Stéphane F.; Wu, Xudong; Hirose, Keiko; Jones, Sherri M.; Bayazitov, Ildar T.; Tian, Yong; Mittleman, Guy; Matthews, Douglas B.; Zakharenko, Stanislav S.; Liberman, M. Charles; Zuo, Jian

doi:10.1128/mcb.02051-06

Cited by 55 publications

(85 citation statements)

References 46 publications

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“…27 In line with this, mice lacking Grid1 showed impaired hearing. 28 In addition, Grid1 mRNA was detected in ganglion and bipolar retinal cells, 29 reminiscent of the Grid2 immunostaining profile.…”

Section: Discussionmentioning

confidence: 99%

Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Schil

Meire

Karlstetter

et al. 2015

Genetics in Medicine

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Section: Discussionmentioning

confidence: 99%

Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Schil

Meire

Karlstetter

et al. 2015

Genetics in Medicine

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“…␦1 is expressed widely in young mice, but the distribution of ␦1 expression is restricted in mature animals (12,15). Thus, ␦1 might play some roles in the synapse formation during development, although the behavioral and neurological abnormalities in ␦1 knockout mice reported so far are confined to mild defects in the auditory ability (15).…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

“…However, it was reported that glutamate binds to neither ␦1 nor ␦2, and whether ␦1 or ␦2 constitutes a functional ion channel is unknown (12)(13)(14). ␦1 is expressed widely in the central nervous system of young mice, but in mature animals expression of ␦1 is confined to the hippocampus, spiral ganglion, and hair cells of inner ears (12,15).Here, we have examined roles of ␦2 and ␦1 in the induction of presynaptic terminal differentiation and synapse formation using a coculture preparation of cerebellar neurons and nonneuronal human embryonic kidney (HEK) cells expressing ␦2, ␦1, etc. We found that the extracellular LIVBP domain of ␦2 induced differentiation of glutamatergic presynaptic terminals and contributed to the establishment of synaptic transmission.…”

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confidence: 99%

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Postsynaptic glutamate receptor δ family contributes to presynaptic terminal differentiation and establishment of synaptic transmission

Kuroyanagi

Yokoyama

Hirano

2009

Proc. Natl. Acad. Sci. U.S.A.

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Synaptic adhesion molecules such as neuroligin are involved in synapse formation, whereas ionotropic transmitter receptors mediate fast synaptic transmission. In mutant mice deficient in the glutamate receptor ␦2 subunit (␦2), the number of synapses between granule neurons (GNs) and a Purkinje neuron (PN) in the cerebellum is reduced. Here, we have examined the role of ␦2 in synapse formation using culture preparations. First, we found that the size and number of GN presynaptic terminals on a PN in the primary culture prepared from knockout mice were smaller than those in control culture. Next we expressed ␦2 in nonneuronal human embryonic kidney (HEK) cells and cocultured them with GNs. Punctate structures expressing marker proteins for glutamatergic presynaptic terminals were accumulated around the HEK cells. Furthermore, HEK cells expressing both ␦2 and GluR1, a glutamate receptor subunit forming a functional glutamate-gated ion channel, showed postsynaptic current. Deletion of the extracellular leucine/isoleucine/valine binding protein (LIVBP) domain of ␦2 abolished the induction ability, and the LIVBP domain directly fused to a transmembrane sequence was sufficient to induce presynaptic differentiation. Furthermore, a mutant GluR1 whose LIVBP domain was replaced with the ␦2 LIVBP domain was sufficient by itself to establish synaptic transmission. Another member of ␦ glutamate receptor family ␦1 also induced presynaptic differentiation. Thus, the ␦ glutamate receptor subfamily can induce the differentiation of glutamatergic presynaptic terminals and contribute to the establishment of synaptic transmission.cerebellum ͉ granule neuron ͉ Purkinje neuron ͉ synapse formation S ynapse formation requires the accumulation and organization of multiple proteins on both the pre-and postsynaptic sides (1, 2). Previous studies have shown that expression of postsynaptic neuroligin in a nonneuronal cell triggers presynaptic differentiation in a contacting axon through interaction with presynaptic neurexin (3, 4). The involvement of other synaptic adhesion proteins, such as SynCAM and cadherin, in the formation or maintenance of synaptic structures has also been reported (5-7). For synaptic function, the most important postsynaptic proteins are receptors for neurotransmitters. Glutamate is the most prevalent neurotransmitter in the central nervous system, and there are ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors on the postsynaptic membrane. iGluR opens its pore domain to allow the permeation of cations when bound by glutamate, and mediates fast excitatory synaptic transmission (8, 9).So far, iGluR has not been shown to be directly related to synapse formation. However, in mutant mice deficient in the glutamate receptor ␦2 subunit (␦2), the number of synapses between granule neurons (GNs) and a Purkinje neuron (PN) is reduced, suggesting the involvement of ␦2 in synapse formation or maintenance (10, 11). ␦2 is selectively expressed in cerebellar PNs and has been classified as a member of the...

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“…The GluD1 KO mice were obtained from Dr. Jian Zuo (St. Jude Children's Hospital, Memphis, TN) (Gao et al, 2007) and maintained as previously described (Yadav et al, 2012) at a constant temperature (22 6 1°C) and a 12-hour light-dark cycle with free access to food and water. Only male mice were used for these studies.…”

Section: Animalsmentioning

confidence: 99%

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

et al. 2016

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The delta family of ionotropic glutamate receptors consists of glutamate delta-1 (GluD1) and glutamate delta-2 receptors. We have previously shown that GluD1 knockout mice exhibit features of developmental delay, including impaired spine pruning and switch in the N-methyl-D-aspartate receptor subunit, which are relevant to autism and other neurodevelopmental disorders. Here, we identified a novel role of GluD1 in regulating metabotropic glutamate receptor 5 (mGlu5) signaling in the hippocampus. Immunohistochemical analysis demonstrated colocalization of mGlu5 with GluD1 punctas in the hippocampus. Additionally, GluD1 protein coimmunoprecipitated with mGlu5 in the hippocampal membrane fraction, as well as when overexpressed in human embryonic kidney 293 cells, demonstrating that GluD1 and mGlu5 may cooperate in a signaling complex. The interaction of mGlu5 with scaffold protein effector Homer, which regulates mechanistic target of rapamycin (mTOR) signaling, was abnormal both under basal conditions and in response to mGlu1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) in GluD1 knockout mice. The basal levels of phosphorylated mTOR and protein kinase B, the signaling proteins downstream of mGlu5 activation, were higher in GluD1 knockout mice, and no further increase was induced by DHPG. We also observed higher basal protein translation and an absence of DHPG-induced increase in GluD1 knockout mice. In accordance with a role of mGlu5-mediated mTOR signaling in synaptic plasticity, DHPG-induced internalization of surface a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits was impaired in the GluD1 knockout mice. These results demonstrate that GluD1 interacts with mGlu5, and loss of GluD1 impairs normal mGlu5 signaling potentially by dysregulating coupling to its effector. These studies identify a novel role of the enigmatic GluD1 subunit in hippocampal function.

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Orphan Glutamate Receptor δ1 Subunit Required for High-Frequency Hearing

Cited by 55 publications

References 46 publications

Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Early-onset autosomal recessive cerebellar ataxia associated with retinal dystrophy: new human hotfoot phenotype caused by homozygous GRID2 deletion

Postsynaptic glutamate receptor δ family contributes to presynaptic terminal differentiation and establishment of synaptic transmission

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

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