Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Delta Glutamate Receptor (GluD1, GluD2)

  • Kazuhisa Kohda
  • Wataru Kakegawa
  • Michisuke Yuzaki
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_642

Synonyms

Historical Background

The δ1 glutamate receptor (GluRδ1 and GluD1) and the δ2 glutamate receptor (GluRδ2 and GluD2) were cloned by homology screening in 1993 at the end of the “gold rush” for cloning of ionotropic glutamate receptor (iGluR) cDNA. They were regarded as orphan receptors for a long time since their endogenous ligands were unknown. GluD1 is highly expressed in hair cells of the auditory and vestibular systems in adult mice. Indeed, deletion of a gene encoding GluD1 (grid1) in mice leads to deficit in high-frequency hearing. In contrast, GluD2 is predominantly expressed in cerebellar Purkinje cells and deletion of a gene encoding GluD2 (grid2) results in cerebellar ataxia and characteristic phenotypes at parallel fiber (PF)–Purkinje cell synapses. Functionally, the long-term depression (LTD) of synaptic transmission, which is thought to underlie motor coordination and motor learning, is completely blunted. Morphologically, approximately 40% of dendritic spines of grid2-null Purkinje cells remain uninnervated by PF terminals. Although these characteristic phenotypes of grid1-null and grid2-null mice point to essential roles played by GluD1 and GluD2, mechanisms by which GluD1/2 mediate these functions remained obscure. Recent structural studies and phenotype rescue experiments have greatly advanced our understanding of mechanistic aspects of GluDs, especially GluD2. For some original references, which have been omitted in this entry for the sake of space, please refer to reviews elsewhere (Yuzaki 2008).

Genes and Expression

The size of grid1 and grid2 genes is much larger (~760 kb for grid1 and ~1.4Mb for grid2 in mice) than sizes of genes encoding other iGluRs (~200 kb). This large size and a high percentage of purine nucleotides within the locus are thought to render grid2 susceptible to frequent spontaneous mutations in mice, called hotfoot (Yuzaki 2008). Human cases that carries mutations in the GRID2 gene have not been discovered until recently (Hills et al. 2013; Utine et al. 2013; Maier et al. 2014; Van Schil et al. 2015; Coutelier et al. 2015). Their overlapping neurological phenotypes included oculomotor impairment, gross motor delay, language and intellectual deficit, and progressive cerebellar atrophy, suggesting that GluD2 also works in the cognitive processes in addition to motor control and learning.

It should be noted that GluD2 expression is not confined to cerebellar Purkinje cells. It has also been reported that interneurons in the cerebellum expressed GluD2 using Purkinje cell-specific grid2-null mice (Yamasaki et al. 2011). Furthermore, immunohistochemical and Western blotting analyses indicated that GluD2 was widely expressed in the brain including olfactory bulb, cerebral cortex, hippocampus, thalamus, striatum, and midbrain (Yuzaki 2008, Hepp et al. 2015, Konno et al. 2014). Thus, although it is proposed that the cerebellum also contributes to cognitive and emotional function (Buckner 2013), it is still unclear which brain regions are responsible for the cognitive impairments derived from GluD2 mutations.

No spontaneous mutant mouse linked to the grid1 locus is known so far. However, recent genome-wide association studies indicated linkage of the GRID1 gene with bipolar disorder, major depressive disorder, and schizophrenia (Fallin et al. 2005; Guo et al. 2007; Treutlein et al. 2009). Furthermore, genome-wide copy number variation studies have implicated that GRID1 may be associated with autism spectrum disorder (ASD; Glessner et al. 2009; Smith et al. 2009).

In addition to hair cells, GluD1 is highly expressed in molecular layer interneurons in the cerebellum (Konno et al. 2014). Furthermore, GluD1 is widely expressed at a low level in the adult mouse brain, including the cerebral cortex, striatum, hippocampus, lateral habenula, and amygdala (Konno et al. 2014). Interestingly, grid1-null mice showed aberrant emotional and social behaviors, other than hearing deficits (Yadav et al. 2012, Yadav et al. 2013). Although the mechanisms are still largely unknown, GluD1 is likely involved in cognitive function and its dysfunction might be associated with mental disorders including schizophrenia, mood disorders, and ASD.

Structure and Function

On the basis of sequence homology with other iGluRs, the topology of GluD1/2 in the cell membrane is predicted to be similar to that of other iGluRs, which are composed of an N-terminal domain (NTD) and a bipartite ligand-binding domain (LBD) on the extracellular side of the plasma membrane, three transmembrane (TM) domains (TM1, TM3, and TM4), an ion channel-forming re-entrant loop segment (TM2 or P-loop), and a cytoplasmic C-terminal domain (CTD) (Fig. 1). GluD2 and GluD1 likely form a homomeric complex in vivo, although it is possible that a small proportion of GluD1 or GluD2 exists as a heteromer with other iGluRs, as observed in vitro (Yuzaki 2008).
Delta Glutamate Receptor (GluD1, GluD2), Fig. 1

Presumed membrane topology of GluD2. The ligand-binding domain (LBD) is separated by transmembrane (TM) domains 1 through 3. The ligand-binding pocket, to which d-serine binds, is indicated by an arrow. Cbln1 binds to the most N-terminal domain (NTD) outside of the LBD (indicated by an arrow). The channel pore is indicated by a dotted circle. The most C-terminal domain (CTD) of GluD2 constitutes a PDZ ligand motif, to which PDZ proteins such as PSD-93, PTPMEG, S-SCAM, n-PIST, and delphilin bind

Extracellular N-Terminal Domain (NTD)

The NTD of iGluRs contributes to receptor assembly and efficient surface transport of the receptor. Similarly, various small inframe deletions in the NTD of GluD2 found in many hotfoot mutant mice impair the homomeric oligomerization of GluD2 and its subsequent exit from the endoplasmic reticulum to reach the cell surface (Yuzaki 2008). These findings suggest that, like other iGluRs, the NTD of GluD2 is essential for receptor assembly, and that unstable oligomers may be retained in the endoplasmic reticulum by the quality control mechanism.

Virally mediated expression of wild-type GluD2 or chimeric glutamate receptor 6 (GluK2) that had the NTD of GluD2 completely rescues impaired PF synaptogenesis in grid2-null mice, while expression of GluD2 lacking the NTD or the chimeric GluD2 with the NTD of GluK2 does not (Table 1). Thus, the NTD of GluD2 is necessary and sufficient for synapse formation between PFs and Purkinje cells (Kakegawa et al. 2009). Interestingly, the NTD of GluD2 was shown to bind to  Cbln1, which is secreted from cerebellar granule cells (Matsuda et al. 2010).  Cbln1 also binds to neurexin on the presynaptic terminals (Matsuda and Yuzaki 2011). These findings indicate that the NTD of GluD2 plays a crucial role in formation and maintenance of PF synapses by forming a tripartite complex consisting of GluD2,  Cbln1, and neurexin at PF-Purkinje cell synapses. Indeed, the recent structural study revealed that GluD2 NTD dimers tether Cbln1 hexamers to monomeric neurexin, indicating that neurexin-Cbln1-GluD2 trimeric complex has a stoichiometry with 2 (in monomer) : 2 (in hexamer) : 1 (in tetramer) (Fig. 2) (Elegheert et al. 2016). Since  Cbln1 also bind to the NTD of GluD1 to promote synaptogenesis in cultured hippocampal neurons (Matsuda et al. 2010; Matsuda and Yuzaki 2011), the NTD of GluD1 may also play a similar role in neurons expressing GluD1.
Delta Glutamate Receptor (GluD1, GluD2), Table 1

Summary of grid2-null phenotypes rescued by various grid2 transgenes

Mouse

Transgene

Disruptedfunction/deleted domain

Age

Method

Ataxia

Motor learning1

Synapse formation

LTD

WT

None

 

Young/Adult

 

e,r

grid2-null

None

 

Young/Adult

 

e,r

+GluD2WT

 

Young/Adult

Virus vector/TG mouse

e,r

+GluD2ΔNT

N-terminal domain (NTD)

Adult

Virus vector

√*

n.e.

+GluD2R/K

Ligand-binding domain (LBD)

Adult

TG mouse

r

Young

TG mouse

r

+GluD2Q/R

Ca2+ permeability

Adult

TG mouse

n.e.

√*

+GluD2V/R

Channel function

Adult

Virus vector

n.e.

Young

Virus vector

n.e.

n.e.

+GluD2ΔCT7

PDZ ligand

Adult

Virus vector/

TG mouse

e,r

rescued, √* partially rescued, not rescued, n.e. not examined

1Motor learning was examined by the delayed eyeblink conditioning test (e) or the rotor-rod test (r)

Delta Glutamate Receptor (GluD1, GluD2), Fig. 2

Neurexin-Cbln1-GluD2 trimeric complex connecting pre- and postsynaptic neurons. GluD2 NTD dimers tether Cbln1 hexamers to monomeric neurexin, indicating that neurexin-Cbln1-GluD2 tripartite complex has a stoichiometry of 2 monomers: 2 hexamers: 1 tetramer. The complex dynamically regulates synapse formation and synapse plasticity in the cerebellum

Extracellular Ligand-Binding Domain (LBD)

An arginine (R) residue highly conserved in the LBD of iGluRs is essential for binding to amino acid ligands, including glutamate, aspartate, glutamine, glycine, lysine, serine, arginine, ornithine, and histidine. Surprisingly, the mutant GluD2 transgene (GluD2R/K), in which the conserved arginine is replaced by lysine (K) to lose the ability of ligand binding, still rescues all the abnormal phenotypes of adult grid2-null mice (Table 1) (Hirai et al. 2005). Therefore, no l-glutamate analog binding is likely required for GluD2 to achieve its functions at least in adult mice.

The LBD of GluD2 was crystallized and shown to bind to d-serine (Fig. 1) in a manner dependent on the arginine residue (Naur et al. 2007). Thus, d-serine fails to bind to GluD2R/K. Interestingly, grid2-null mice expressing GluD2R/K exhibited impaired LTD and motor dyscoordination during development (Kakegawa et al. 2011). Indeed, d-serine is released from Bergmann glia after the burst stimulation of PFs in immature, but not mature, cerebellum because of developmental upregulation of d-amino acid oxidase, a d-serine-degrading enzyme. These findings indicate that d-serine serves as an endogenous ligand for GluD2 in immature cerebellum. Recently, this d-serine-GluD2-mediated LTD signaling is reportedly influenced by binding of Cbln1 to the GluD2 NTD, suggesting that potential NTD-LBD coupling is crucial for d-serine-dependent LTD (Elegheert et al. 2016). Although d-serine also binds to GluD1 (Yadav et al. 2011), its physiological significance remains to be determined.

Channel Pore-Forming Domain

A point mutation in the TM3 of GluD2 (GluD2 Lc ) makes GluD2 channel constitutively open, causing Purkinje cell death in lurcher mice (Zuo et al. 1997). The Ca2+ permeability of GluD2 Lc is abolished by replacing glutamine (Q) with arginine (R) at the Q/R site (GluD2Q/R) (Kohda et al. 2000; Kakegawa et al. 2007a). However, when a mutant GluD2Q/R transgene is introduced into grid2-null Purkinje cells, LTD and other major abnormalities of grid2-null mice are rescued (Table 1). These finding indicate that although cerebellar LTD depends on Ca2+ influx, GluD2 unlikely serves as a Ca2+-permeable channel (Kakegawa et al. 2007a).

The channel activity of GluD2 Lc is abolished by replacing valine (V) with arginine (R) at one position upstream of the Q/R site (GluD2V/R) (Kakegawa et al. 2007b). Surprisingly, the expression of GluD2V/R in grid2-null Purkinje cells by Sindbis virus completely restored LTD and motor coordination (Table 1), indicating that channel activity of GluD2 is not required for inducing LTD.

Together, although channel activities do not seem required to achieve major functions of GluD2 at PF-Purkinje cell synapses, there still remains a possibility that GluD2 might function as an ion channel under some circumstances (Ady et al. 2014).

Cytoplasmic C-Terminal Domain (CTD)

The cytoplasmic CTD of GluD2 binds to many intracellular proteins such as Shank, PICK1, and the adaptor protein complex  AP-4. In addition, the most CTD of GluD2 constitutes a PDZ ligand motif, to which PDZ proteins, such as PSD-93, PTPMEG, S-SCAM, n-PIST, and delphilin, bind (Yuzaki 2008). When the mutant GluD2 lacking the C-terminal seven amino acids (GluD2ΔCT7) is expressed in grid2-null PCs, it fails to rescue abrogated LTD and impaired delayed eyeblink conditioning, a cerebellum-dependent motor learning, in grid2-null mice (Table 1) (Kohda et al. 2007; Kakegawa et al. 2008). Furthermore, d-serine binding to GluD2 failed to induce LTD when the CTD is deleted (Kakegawa et al. 2011). In contrast, the mutant transgene GluD2ΔCT7 completely restores abnormal PF synapse formation (Kakegawa et al. 2008). These findings indicate that signaling via the CTD of GluD2 is not necessary for morphological integrity at PF synapses, but absolutely required for the induction of LTD and motor learning.

How is the CTD of GluD2 involved in the signaling for cerebellar LTD? PTPMEG, a tyrosine phosphatase, binds to the most C-terminus of GluD2 and PTPMEG-null mice showed impaired cerebellar LTD (Kina et al. 2007). It was found that PTPMEG directly dephosphorylated tyrosine 876 (Y876) of the AMPA receptor’s GluA2 subunit in vitro and a chemical LTD stimulus mimicking the depolarization of Purkinje cells and the activation of PF inputs significantly reduced Y876 phosphorylation in wild-type mice, while it remained unchanged in grid2- and PTPMEG-null mice (Kohda et al. 2013). In addition, Y876 phosphorylation significantly attenuated subsequent phosphorylation of serine 880 of GluA2 by PKC (Kohda et al. 2013), which is an essential step for activity-dependent endocytosis of AMPA receptors, a molecular substrate of LTD (Matsuda et al. 2000). Therefore, direct interaction between GluD2 and PTPMEG likely reduces Y876 phosphorylation of GluA2, thereby enabling activity-dependent GluA2 S880 phosphorylation and LTD (Fig. 3). Although d-serine-mediated LTD also requires GluD2 CTD (Kakegawa et al. 2011), it remains unclear whether dephosphorylation of GluA2-Y876 by PTPMEG is involved in this process.
Delta Glutamate Receptor (GluD1, GluD2), Fig. 3

GluD2-CTD signaling for cerebellar LTD. (Top) In wild-type mice, GluD2 maintains low phosphorylation levels at tyrosine 876 (Y876) of the AMPA receptor’s GluA2 subunit through PTPMEG, a tyrosine phosphatase binding to the most C-terminus of GluD2. An LTD-inducing stimulation (LTD-stim.) further reduces Y876 phosphorylation allowing PKC to phosphorylate serine 880 (S880) of GluA2, which is an essential step for activity-dependent endocytosis of AMPA receptors, a molecular substrate of LTD. (Bottom) In grid2-null mice, PTPMEG fails to dephosphorylate Y876 of GluA2, thereby impairing S880 phosphorylation and LTD

Summary

Although GluD2 was referred to an orphan receptor for a long time, it now has two unusual endogenous ligands –  Cbln1 and d-serine. The extracellular NTD of GluD2 plays a crucial role in the formation and maintenance of PF synapses by forming a tripartite complex with  Cbln1 and its presynaptic receptor neurexin in the cerebellum. On the other hand, the LBD of GluD2 binds to d-serine, which is released from cerebellar Bergman glia during early developmental period, to facilitate LTD and motor coordination. Although signaling via interactions of the CTD of GluD2 and PTPMEG is required for the induction of LTD and motor learning, how and whether PTPMEG activity is regulated remains unanswered. In addition, how Cbln1 binding to the NTD and d-serine binding to the LBD induce conformational changes to the whole GluD2 complex and transmit signals to the CTD and its interacting proteins remain to be determined. Finally, although  Cbln1 (and Cbln2, Cbln4) and d-serine bind to GluD1, it is currently unclear whether GluD1 regulates synaptic functions similar to those exerted by GluD2 in various brain regions in vivo.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Kazuhisa Kohda
    • 1
    • 2
  • Wataru Kakegawa
    • 1
  • Michisuke Yuzaki
    • 3
  1. 1.Department of NeurophysiologyKeio University School of MedicineShinjuku-kuJapan
  2. 2.Department of PhysiologySt. Marianna University School of MedicineKawasakiJapan
  3. 3.Department of NeurophysiologySchool of Medicine, Keio UniversityShinjuku-ku, TokyoJapan