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|Coordinate||64,395,280 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||glutamate receptor, ionotropic, delta 2|
|Synonym(s)||GluRdelta2, tpr, B230104L07Rik|
|Chromosomal Location||63,255,876-64,704,323 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain. The encoded protein is a multi-pass membrane protein that is expressed selectively in cerebellar Purkinje cells. A point mutation in the mouse ortholog, associated with the phenotype named 'lurcher', in the heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis. This protein also plays a role in synapse organization between parallel fibers and Purkinje cells. Alternate splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause cerebellar ataxia in humans. [provided by RefSeq, Apr 2014]
PHENOTYPE: Homozygotes for multiple spontaneous and targeted null mutations exhibit ataxia and impaired locomotion associated with cerebellar Purkinje cell abnormalities and loss, and on some backgrounds, male infertility due to lack of zona penetration by sperm. [provided by MGI curators]
|Amino Acid Change||Tyrosine changed to Stop codon|
|Institutional Source||Beutler Lab|
Y648* in Ensembl: ENSMUSP00000093536 (fasta)
|Gene Model||not available|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Embryos, Sperm, gDNA|
|Last Updated||2018-05-22 9:43 AM by Anne Murray|
The swagger phenotype was identified in three littermates among ENU-mutagenized G3 mice. Homozygous swagger mice appear somewhat lethargic, with a wobbling gait that is more pronounced upon movement. They have trouble keeping balance and exhibit an altered gait characterized by exaggerated high stepping of the hind legs. Swagger mice can swim well; hind limbs perform actively in the water. Homozygous male mice are sterile.
|Nature of Mutation|
The swagger mutation was mapped to Chromosome 6, and corresponds to a T to A transversion at position 1944 of the Grid2 transcript, in exon 12 of 16 total exons.
The mutated nucleotide is indicated in red lettering, and converts the codon for tyrosine 648 to a stop codon.
Glutamate receptor ion channels (ionotropic glutamate receptors, iGluR), which are nonselective for monovalent cations (and sometimes Ca2+ permeable), are the major mediators of excitatory synaptic transmission in the central nervous system. Three subtypes, the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate), kainate, and NMDA (N-methyl-D-aspartate) receptors, were identified pharmacologically, based on their activation by the exogenous agonists after which they are named. A fourth subfamily, which consists of the δ1 and δ2 glutamate receptors (GluRδ1 and GluRδ2), was discovered in 1993 by low stringency screening of mouse and rat brain cDNA libraries using AMPA receptor probes (1-3). The amino acid sequences of GluRδ1 and GluRδ2 are 56% identical to each other, approximately 20-25% identical to AMPA and kainate receptors, and approximately 15-20% identical to NMDA receptors (2;3).
Bacterial expression of the AMPA receptor GluR2 S1 and S2 segments joined by a linker produces a soluble, crystallizable protein representing the LBD (5;16;17), a strategy also used to crystallize the putative LBD of GluRδ2 (18). These studies revealed that S1 and S2 form a clam shell-like structure with two lobes, designated D1 and D2. S1 and S2 each contribute amino acids to both lobes. In the GluR2 LBD structure, the agonist binding site is located in the opening between the two lobes. Most iGluR agonists, such as glutamate, AMPA, and kainate, are amino acids, and their α-amino and α-carboxyl groups dock on the D1 lobe. D2 is then attracted by the γ-carboxyl group and rotates (approximately 21° for glutamate or AMPA binding to GluR2) to close the clam shell structure, locking the agonist in its binding pocket. Thus, agonist binding activates the receptor by inducing a switch from a relaxed, expanded conformation in which the two lobes are open, to a closed conformation that sequesters the agonist in the cleft between lobes. Full agonists induce tighter closure of the D1 and D2 lobes than partial agonists (5). Receptor dimers are held together by extensive interactions between D1 residues from their LBDs.
The transmembrane regions of iGluRs form the ion channel pore, and consist of three α-helices (M1, M3, and M4) and a membrane-inserted pore loop (P or M2) (Figure 1). The pore loop determines the ion selectivity of the channel pore (20). The amino acid sequence of the channel pore is highly homologous to that of K+ channels, to which it is related evolutionarily (21;22) (see the record for mayday that describes Kir6.1, a member of inwardly rectifying K+ channels). However, in all iGluRs the channel orientation in the membrane is inverted compared to that of classical K+ channels, and contains an extra transmembrane helix (M4) with essential but unknown function (20;23). In addition, iGluRs are arranged as a dimer of dimers (4-6), while K+ channels are tetramers with four-fold symmetry. The major pore-lining domain of glutamate receptors is the M3 helix, which corresponds to the inner or M2 helix of K+ channels, and is extensively involved in channel gating (24-26). In the NMDA receptor, M3 domains allosterically interact with both the channel gate and the LBD and mediate their coupling, such that ligand binding changes the conformation of TM3 and in turn the probability of channel opening (26). Present in the M3 domain of all glutamate receptors is the sequence motif SYTANLAAF, which is the most highly conserved motif among glutamate receptors. Mutation of residues in this motif strongly alter channel function (24;25).
The swagger mutation occurs within the most highly conserved iGluR motif, the SYTANLAAF sequence within the M3 helix, and converts the tyrosine residue to a stop.
GluRδ2 mRNA is exclusively expressed in Purkinje cells of the cerebellum (2;3)(Figure 3). In the adult rat brain, an antibody against a C-terminal domain peptide (also reactive against GluRδ1) detects GluRδ2 reactivity most strongly in the cerebellum, and there in Purkinje cell bodies and postsynaptic densities of spines forming synapses with parallel fibers (27). GluRδ2 mRNA is expressed as early as embryonic day 15 in Purkinje cell neuroblasts (28), but Western blotting shows little cerebellar protein expression until postnatal day 15, when GluRδ2 is dramatically upregulated (27). GluRδ2 appears to be expressed in both dendritic shafts and spines in the early postnatal period, but by postnatal day 21 when Purkinje cells have reached maturity, GluRδ2 becomes restricted to dendritic spines (28;29). Within spines, GluRδ2 is most highly localized at the postsynaptic density of synapses with parallel fibers.
Purkinje cells receive two types of excitatory input, from parallel fibers of granule cells in the granular layer of the cerebellum, or climbing fibers that originate from inferior olivary neurons in the brainstem. Both types of input develop during the first two postnatal weeks, although the timecourse of development differs between them. Climbing fibers begin forming synapses by postnatal day 2, while parallel fibers begin between postnatal days 7-10. Inputs from climbing fibers are restricted to the proximal dendrites of Purkinje cells; parallel fibers synapses are found on the distal portion of the dendritic tree. At postnatal day 10, GluRδ2 is expressed in both climbing fiber and parallel fiber synapses, but by adulthood, its expression becomes restricted to parallel fiber synapses (30-32). This selective targeting of GluRδ2 to parallel fiber synapses is activity-dependent. Block of neuronal activity with tetrodotoxin (TTX) induces a redistribution of GluRδ2 to all Purkinje cell spines (33).
GluRδ2 has also been detected in a population of glial-like cells in rat pineal glands in culture (34).
The amino acid glutamate is the major excitatory amino acid in the mammalian brain, mediating an estimated 50% of all synaptic transmission in the CNS [reviewed in (35)]. Glutamate is synthesized, stored, released from the presynaptic terminal, and acts through both ligand-gated ion channels (ionotropic glutamate receptors) and G-protein coupled receptors (metabotropic glutamate receptors) on postsynaptic neurons. Activation of these receptors accounts for basal excitatory synaptic transmission and synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) that are thought to underlie learning and memory. Glutamatergic synaptic transmission is implicated in nearly all aspects of normal brain function, including learning, memory, movement, cognition, and development. However, at elevated concentrations that excessively stimulate the same receptors, glutamate acts as a neurotoxin capable of causing extensive neuronal damage and death. Thus, the brain maintains very low intrasynaptic concentrations of glutamate by the action of glutamate transporters present in the plasma membrane of both glial cells and neurons.
An array of receptors representing homo- and heteromers of the three subtypes of glutamate receptor is present on neuronal membranes, and transduces signals through increased ion flux and second messenger signaling pathways (see Protein Prediction). The glutamate receptor ion channels display distinct electrophysiological properties, including channel selectivity for Na+, K+, and Ca2+. Glutamate receptors are also characterized by their pharmacological profiles, including sensitivity to glutamate analogues and by the features of the glutamate-elicited current. In these aspects, the two GluRδ proteins, designated as glutamate ion channels based on their sequence similarity to other iGluRs, remain mysterious (1-3). Both GluRδ1 and GluRδ2 are insensitive to common iGluR agonists, and so far no ligand able to activate the wild type channel has been identified (3;18;27).
The discovery that the phenotype of Lurcher (Lc) mice is caused by a point mutation in GluRδ2 was an enormous breakthrough in the study of these channels (36). The Lurcher mutation is an alanine to threonine point mutation of the third alanine (A654) within the SYTANLAAF sequence motif of GluRδ2 (36). GluRδ2Lc mutant channels are spontaneously active, permitting a large constitutive cationic current in the absence of ligand. Since no GluRδ2 agonists are known, all electrophysiological characterization of GluRδ2 receptors has focused on the spontaneous activity of mutant channels with the Lurcher mutation. Examination of the current-volage relationship revealed that GluRδ2Lc channel currents are doubly rectified, in that current flows more easily at membrane potentials lower than +20 mV or higher than +70 mV (25;37). This property resembles that of AMPA and kainate receptors which contain, like GluRδ2, a glutamine residue at the tip of the pore loop. Spontaneous current through Lurcher channels is potentiated by extracellular Ca2+ (37), whereas extracellular protons reduce current flow as they do for the NMDA receptor (38). The open GluRδ2Lc channels are blocked by several chemicals that also inhibit NMDA receptors (pentamidine; 9-tetrahydroaminoacridine, 9-THA) (38).
The mechanisms of GluRδ2Lc-induced Purkinje cell death have yet to be definitively established, although much research has focused on this topic [reviewed in (46)]. Studies suggest that Lurcher Purkinje cells are apoptotic, as demonstrated by TUNEL staining, increased Bax and Bcl-x expression, and increased pro-caspase 3 levels (47-49). In addition, GluRδ2Lc has been proposed to trigger an autophagic cell death pathway through its failure to sequester the PDZ/coiled domain protein n-PIST and the Bcl-2-interacting protein Beclin (50). Autophagosome-like vesicles have been observed in Lc/+ Purkinje cells (50;51). However, the steps leading from autophagy to death in Lc/+ Purkinje cells are unknown. Increased oxidative stress may also contribute to Purkinje cell death in Lurcher mice (52).
The importance of GluRδ2 for other Purkinje cell functions has been demonstrated using mice with a targeted deletion of the protein. GluRδ2-deficient mice display impaired motor coordination, with ataxia observable by postnatal day 12 (53). These mice walk with tottering steps, and lose balance and roll when they rear up on their hind legs. In general they are less active than their wild type littermates. When made to walk on a narrow, elevated runway, Grid2-/- mice walk slowly and frequently slip, unlike wild type mice that run quickly with few slips. Grid2-/- mice also fall off a rotating rod more quickly than wild type mice. The cerebellum of adult Grid2-/- mice shows a normal architecture and characteristic cellular organization, and Purkinje cells have dendritic arbors comparable in size and in number of spines to those of wild type mice. However, the number of spines forming synapses with parallel fibers is reduced by half, aberrant multiple innervation of Purkinje cells by climbing fibers persists in the adult (a one-to-one climbing fiber to Purkinje cell innervation is normal), and numerous free spines are found (54-56). In mice with a floxed allele of Grid2, induction of Cre recombinase specifically in GluRδ2-expressing cells, resulted in progressive shrinking of parallel fiber presynaptic active zones, mismatching between presynaptic active zones and Purkinje cell postsynaptic densities, and the emergence of free spines (57). Together, these findings suggest that GluRδ2 contributes to the stabilization of parallel fiber-Purkinje cell synapses, restricts climbing fiber synapses to proximal dendrites, and prevents ectopic climbing fiber synapse formation.
Long term depression (LTD), the persistent, activity-dependent depression of synaptic transmission, is the main form of synaptic plasticity at the parallel fiber-Purkinje cell synapse. GluRδ2 is required for cerebellar LTD, as shown in GluRδ2-deficient cerebellar slices and in cerebellar cultures after knockdown of GluRδ2 expression (53;58;59). LTD is thought to underlie motor learning, and Grid2-/- mice display defects in eye movement, blink conditioning and vestibular compensation (60-62), and develop involuntary spontaneous eye movements synchronized with action potential firing by Purkinje cells (63). Surprisingly, transgenic expression of mutant GluRδ2 proteins in GluRδ2-deficient mice suggest that the CTD, but not the ligand-binding or ion channel capabilities of GluRδ2, is necessary for LTD (64-66). Functional studies with a blocking antibody showed that GluRδ2 may regulate LTD by controlling AMPA receptor endocytosis (67).
The 172 amino acid C-terminus of GluRδ2 interacts with a variety of postsynaptic proteins in yeast two-hybrid experiments, several of which are essential for the induction of LTD. GluRδ2 binds directly to the PDZ domain of Shank proteins, which are linked to AMPA receptors via glutamate receptor interacting protein 1 (GRIP1) and to mGluR1 via Homer (68). The CTD of GluRδ2 has also been shown to interact with protein interacting with C kinase 1 (PICK1), a protein required for LTD (69). Finally, GluRδ2 interacts with the MAGUK (membrane-associated guanylate kinase) S-SCAM (synaptic scaffolding molecule), an interaction enhanced upon phosphorylation of the receptor by PKC after LTD induction (14). Despite the identification of numerous interactors, the role of GluRδ2 in LTD is not understood.
The phenotype of swagger mice resembles those of Grid2-/- mice, as well as heterozygous Lurcher mice. Although protein expression of GluRδ2 has not been examined, two reasons suggest that the swagger mutation results effectively in a protein null phenotype rather than a gain-of-function phenotype causing massive Purkinje cell death such as that observed in Lurcher mice. First, the mutation creates a premature stop codon, which is likely to disrupt protein stability and lead to degradation. Second, like the Grid2 null allele and the hotfoot alleles (mainly deletions of portions of the CTD), the swagger mutation is recessive. In contrast, the Lurcher mutation causes death when present in homozygous form. Examination of cerebellar architecture has not been performed in swagger mice.
|Primers||Primers cannot be located by automatic search.|
Swagger genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition. This protocol has not been tested.
swagger (F): 5’- TTGTGAATAGCCCAGTCCTTGGAAAC -3’
swagger (R): 5’-CTGTTACTGATGCTAGAGAAAGAGCAGC -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
swagger_seq(F): 5’- GCCCAGTCCTTGGAAACAAAATATG -3’
swagger_seq(R): 5’- GTGACACCTGGAATTATGCCTAC -3’
The following sequence of 1135 nucleotides (from Genbank genomic region NC_000072 for linear genomic sequence of Grid2 [Chr6:64394888-64396022) is amplified:
ttgtgaatag cccagtcctt ggaaacaaaa tatgtatttg tgactataat aaggaattga ttttagaatt aaaggagaaa gaattatcat ttcaatgtat tttgtagaat atttatcatg cttcttttta acacagccag acataattcc atagaagatc atcaaaaacc aagtattaaa atatggaggt ctccagagtt tttaagggaa acgtttcttg ttgtctgtct tggcactgaa tgtgtatgac ttcagtttct caataaaagc atattgatgt tgttgtcatc tctcctcttt ccacaggtgg ggaagtccca tacacaactc tggcaacccg aatgatgatg ggggcttggt ggttatttgc tctgattgtc atctcatctt atacagccaa ccttgccgct ttcctcacta tcacccgcat tgagagctcc atccagtaag taggcataat tccaggtgtc accaaacctg acaaatgctg ggcatgccac aaggaaagcc ctctgcacat aaagttgcac taccttataa taaattgtca ctctcttttt gacaagaagc ttaatcctat gattcttcag aatatcaatc ctaaataatt tattttataa aatgttgatt ataacttaat tctgtatttt cctggaataa taacagatca tcaaaaattt aaccttcata gaggatagct atgtcagggc aggagaaatt attcaaaacc atcctcaact tcatttcaca gagatctcat atcctctatt gactctaaca tcattgcaca tgcatagtga cagacataca tggatgcaga agcataaaat aaaaataagt aaatctttaa acataaacta tgtcagagaa aaattatgaa aaaaaaagta taaataattt taggaaatta aaatgccctt ttttaaaata agtttgtgca atcacagttg atggctaaat ttattctgtg ggtgagggag taaggagaga agaggacaat ggaagataag aagagagagg ggaaaagagg atagcaggta acagaaactc tatcatagtg accacattct gtttcttgtc tgcattaata cccacgtggc caacactgct gctctttctc tagcatcagt aacag
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is indicated in red.
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|Science Writers||Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine|
|Authors||Lei Sun, Alyson Affleck, Bruce Beutler|
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