GRID2

GRID2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 5KCA, 5KC8
Identifiers
Aliases	GRID2, GluD2, SCAR18, glutamate ionotropic receptor delta type subunit 2
External IDs	OMIM: 602368 MGI: 95813 HomoloGene: 74399 GeneCards: GRID2
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q22.1-q22.2 Start 92,303,966 bp[1] End 93,810,157 bp[1]
Gene location (Mouse) Chr. Chromosome 6 (mouse)[2] Band 6 C1|6 29.77 cM Start 63,232,860 bp[2] End 64,681,307 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence corpus callosum nucleus accumbens prefrontal cortex caudate nucleus hypothalamus putamen sural nerve amygdala Brodmann area 9 Top expressed in cerebellar vermis motor neuron substantia nigra facial motor nucleus urethra dorsomedial hypothalamic nucleus female urethra inferior colliculus median eminence dorsal tegmental nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function glutamate receptor activity PDZ domain binding scaffold protein binding ion channel activity ionotropic glutamate receptor activity extracellularly glutamate-gated ion channel activity protein binding signaling receptor activity transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential Cellular component integral component of membrane postsynaptic membrane membrane plasma membrane dendritic spine synapse integral component of plasma membrane cell junction ionotropic glutamate receptor complex somatodendritic compartment parallel fiber to Purkinje cell synapse glutamatergic synapse integral component of postsynaptic density membrane Biological process glutamate receptor signaling pathway heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules regulation of neuron projection development synaptic transmission, glutamatergic regulation of neuron apoptotic process ion transport ion transmembrane transport ionotropic glutamate receptor signaling pathway excitatory postsynaptic potential cerebellar granule cell differentiation prepulse inhibition positive regulation of synapse assembly positive regulation of long-term synaptic depression excitatory synapse assembly regulation of postsynaptic density assembly modulation of chemical synaptic transmission Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2895 14804 Ensembl ENSG00000152208 ENSMUSG00000071424 UniProt O43424 Q61625 RefSeq (mRNA) NM_001286838 NM_001510 NM_008167 NM_001370966 RefSeq (protein) NP_001273767 NP_001501 NP_032193 NP_001357895 Location (UCSC) Chr 4: 92.3 – 93.81 Mb Chr 6: 63.23 – 64.68 Mb PubMed search [3] [4]
Wikidata
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Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ₂, is a protein that in humans is encoded by the GRID2 gene.^[5][6] This protein together with GluD1 belongs to the delta receptor subtype of ionotropic glutamate receptors. They possess 14–24% sequence homology with AMPA, kainate, and NMDA subunits, but, despite their name, do not actually bind glutamate or various other glutamate agonists.^[7]

delta iGluRs have long been considered orphan receptors as their endogenous ligand was unknown. They are now believed to bind glycine and D-serine but these do not result in channel opening.^[8][9]

Function

GluD2-containing receptors are selectively/predominantly expressed in Purkinje cells in the cerebellum^[7][10] where they play a key role in synaptogenesis, synaptic plasticity, and motor coordination.^[11]

GluD2 induces synaptogenesis through interaction of its N-terminal domain with Cbln1, which in turn interacts with presynaptic neurexins, forming a bridge across cerebellar synapses.^[11][12]

The main functions of GluD2 in synaptic plasticity are carried out by its intracellular C-terminus.^[13] This is regulated by D-serine,^[14] which binds to the ligand-binding domain and results in changes in the structure of GluD2 without opening the channel in the absence of pre-synaptic connections.^[9] Glycine and D-serine can open the channel in GluD2 when bound to cerebellin-1 and neurexin-1β.^[15] These changes may signal up to the N-terminal domain or down to the C-terminal domain to alter protein-protein interactions.

Pathology

A heterozygous deletion in GRID2 in humans causes a complicated spastic paraplegia with ataxia, frontotemporal dementia, and lower motor neuron involvement^[16] whereas a homozygous biallelic deletion leads to a syndrome of cerebellar ataxia with marked developmental delay, pyramidal tract involvement^[17] and tonic upgaze,^[18] that can be classified as an ataxia with oculomotor apraxia (AOA) and has been named spinocerebellar ataxia, autosomal recessive type 18 (SCAR18).

A gain of channel function, resulting from a point mutation in mouse GRID2, is associated with the phenotype named 'lurcher', which in the heterozygous state leads to ataxia and motor coordination deficits resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development.^[19][20] Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis.

Ligands

9-Aminoacridine, 9-tetrahydroaminoacridine, N1-dansyl-spermine, N1-dansyl-spermidine, and pentamidine have been shown to act as antagonists of δ₂-containing receptors.^[21]

Interactions

GRID2 has been shown to interact with GOPC,^[22] GRIK2,^[23] PTPN4^[24] and GRIA1.^[23] A possible correlation between GRID2 and the pre-B lymphocyte protein 3 (VPREB3) has been suggested, due to the apparent importance of B-lymphocytes in the origins of cerebellar Purkinje neurons in humans.^{[25][26][27][28][29]} Morphological studies conducted in GRID2-knockout mice suggest that GRID2 may be present in lymphocytes as well as in the adrenal cortex, however further studies must be conducted to confirm these claims.^[28][30]

See also

• GRID1

References

Further reading