5KCA, 5KC8
2895
14804
ENSG00000152208
ENSMUSG00000071424
O43424
Q61625
NM_001286838NM_001510
NM_008167NM_001370966
NP_001273767NP_001501
NP_032193NP_001357895
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, have been found not to directly promote neuronal activation in response to 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]
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.
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.
9-Aminoacridine, 9-tetrahydroaminoacridine, N1-dansyl-spermine, N1-dansyl-spermidine, and pentamidine have been shown to act as antagonists of δ2-containing receptors.[21]
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]