GRIA2

Last updated
GRIA2
Protein GRIA2 PDB 1ftj.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GRIA2 , GLUR2, GLURB, GluA2, GluR-K2, HBGR2, glutamate ionotropic receptor AMPA type subunit 2, gluR-B, gluR-2, NEDLIB
External IDs OMIM: 138247 MGI: 95809 HomoloGene: 20225 GeneCards: GRIA2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000826
NM_001083619
NM_001083620
NM_001379000
NM_001379001

Contents

NM_001039195
NM_001083806
NM_013540
NM_001357924
NM_001357927

RefSeq (protein)

NP_000817
NP_001077088
NP_001077089
NP_001365929
NP_001365930

NP_001034284
NP_001077275
NP_038568
NP_001344853
NP_001344856

Location (UCSC) Chr 4: 157.2 – 157.37 Mb Chr 3: 80.59 – 80.71 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Glutamate ionotropic receptor AMPA type subunit 2 (Glutamate receptor 2, or GluR-2) is a protein that in humans is encoded by the GRIA2 (or GLUR2) gene and it is a subunit found in the AMPA receptors. [5] [6] [7]

Function

Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes. This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), called AMPA receptors, and function as ligand-activated cation channels. These channels are assembled from a combination of 4 subunits, encoded by 4 genes (GRIA1-4). The subunit encoded by this gene (GRIA2) is subject to RNA editing which renders the receptor that it becomes part of impermeable to calcium ions (Ca2+). Human and animal studies suggest that the RNA editing is essential for normal brain function, and defective RNA editing of this gene may be relevant to the etiology of amyotrophic lateral sclerosis (ALS). Alternative splicing, resulting in transcript variants encoding different isoforms, has been noted for this gene, which includes the generation of flip and flop isoforms that vary in their signal transduction properties. [8] [7]

Interactions

GRIA2 has been shown to interact with SPTAN1, [9] GRIP1 [10] and PICK1. [10]

RNA editing

Several ion channels and neurotransmitters receptors pre-mRNA as substrates for ADARs. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2, Glur3, Glur4) and kainate receptor subunits (Glur5, Glur6). Glutamate-gated ion channels are made up of four subunits per channel, with each subunit contributing to the pore loop structure. The pore loop structure is related to that found in K+ channels (e.g., human Kv1.1 channel). [11] The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing. [12] The function of the glutamate receptors is in the mediation of fast neurotransmission to the brain. The diversity of the subunits is determined, as well as RNA splicing by RNA editing events of the individual subunits. This give rise to the necessarily high diversity of these receptors. Glur2 is a gene product of the pre-mRNA of the GRIA2 gene and subject to RNA editing.

Type

The type of RNA editing that occurs in the pre-mRNA of GluR-2 is Adenosine-to-Inosine (A-to-I) editing. [11] A-to-I RNA editing is catalyzed by a family of adenosine deaminases acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine. Inosines are recognised as guanosine by the cells translational machinery. There are three members of the ADAR family ADARs 1-3, with ADAR1 and ADAR2 being the only enzymatically active members. ADAR3 is thought to have a regulatory role in the brain. ADAR1 and ADAR2 are widely expressed in tissues, while ADAR3 is restricted to the brain. The double-stranded regions of RNA are formed by base-pairing between residues in the close to region of the editing site, with residues usually in a neighboring intron, but can be an exonic sequence. The region that base pairs with the editing region is known as an Editing Complementary Sequence (ECS). ADARs bind interact directly with the dsRNA substrate via their double-stranded RNA binding domains. If an editing site occurs within a coding sequence, it can result in a codon change. This can lead to translation of a protein isoform due to a change in its primary protein structure. Therefore, editing can also alter protein function. A-to-I editing occurs in a non coding RNA sequences such as introns, untranslated regions (UTRs), LINEs, SINEs (especially Alu repeats). The function of A to I editing in these regions is thought to involve creation of splice sites and retention of RNAs in the nucleus amongst others.

Location

In the pre-mRNA of GluR-2 the editing site Q/R is found at amino acid position 607. This location is in the pore loop region deep within the ion channel in the proteins membrane segment 2. Editing results in a change from a glutamine(Q) codon to an Arginine (R) codon. Editing at the R/G site, located at amino acid position 764 results in a codon change from arginine to glycine. All editing in glutamate receptors occurs in double-stranded RNAs (dsRNAs), which form due to complementary base pairing between the region of the editing site within the exon and an ECS within an intron sequence. [13] R/G site

Conservation

Regulation

Editing occurs at the Q/R site at a frequency of 100% of GluR2 transcripts in the brain. It is the only known editing site to be edited at a frequency of 100%. [11] However some striatal and cortical neurons are edited less frequently. This has been suggested as a reason for the higher level of excitotoxicity of these particular neurons. [14] The R/G site is developmentally regulated, being largely unedited in the embryonic brain with levels rising after birth. (ref 53)

Consequences

Structure

Editing results in a codon change from a glutamine codon (CAG) to an arginine codon (CIG). [15] Editing at R/G results in a codon change. The region of the editing site is known to be the region that controls divalent cation permeability. The other ionotropic AMPA glutamate receptors have a genomically encoded have a glutamine residue, while GluR2 has an arginine.

Function

RNA editing of the GluR-2 (GluR-B) pre-mRNA is the best-characterised example of A-to-I editing. Activated by L-Glutamate, a major excitatory neurotransmitter in vertebrates central nervous systems, it acts as an agonist at NMDA, AMPA, and kainate neurotransmitters.(103) Activation results in neuronal cation entry (CA2+), causing membrane depolarisation required for the process of excitatory neurotransmission. The calcium permeability of these receptor channels is required for many important events in the CNS, including long-term potentiation.(104) Since editing occurs in nearly 100% of transcripts and is necessary for life, it is often wondered why edited GluR-B is not genomically encoded instead of being derived by RNA editing. The answer is unknown.

RNA editing at the Q/R site is thought to alter the permeability of the channel rendering it impermeable to Ca2+. The Q/R site also occurs in the Kainate receptors GluR5 and GluR6. Editing at the Q/R site determines the calcium permeability of the channel, [11] with channels containing the edited form being less permeable to calcium. This differs from GluR6 where editing of the Q/R site may increase calcium permeability of the channel especially if the I/V and Y/C sites are also edited. Therefore, the main function of editing is therefore in regulation of electrophysiology of the channel. [16]

Editing in some striatal and cortical neurons is more likely to be subject to excitotoxicity, thought to be due to less than 100% editing of these particular neurons. [14] Editing also has several other function effects. Editing alters the maturation and assembly of the channel, with the unedited form having a tendency to tetramerize and then is transported to the synapse. However, the edited version is assembled as a monomer and resides mainly in the endoplasmic reticulum. The arginine residue in the pore loop of GluR-2 receptor is thought to belong to a retention signal for the endoplasmic reticulum. Therefore, editing - since it occurs at 100% frequency - inhibits the availability of the channel at the synapse. This process occurs before assembly of the channels, thereby preventing glur-2-forming homeric channels, which could interfere with synaptic signalling.

Editing also occurs at the R/G site. Editing at the R/G sites results in variation in the rate that the receptor recovers from desensitisation. Editing at these sites results in faster recovery time from desensitisation [17]

Dysregulation

Amyotrophic Lateral Sclerosis

Many human and animal studies have determined that RNA editing of the Q/R site in GluR2 pre-mRNA is necessary for normal brain function. Defective editing has been linked to several conditions such as amyotrophic lateral sclerosis (ALS). ALS effects 1 in 2000 people, usually fatal in 1–5 years, with onset in the majority of cases being sporadic and minority being familial. [18] With these conditions motor neurons degenerate leading to eventual paralysis and respiratory failure. Glutamate excitotoxicity is known to contribute to the spread of the sporadic condition. Glutamate levels are increased up 40%, suggesting that activation of glutamate receptors could be the reason for this causing increase Ca influx and then neuronal death. [19] Since decrease nor loss of editing at Q/R site would lead to increase in calcium permeability. In diseased motor neurons editing levels of Glur 2 (62-100%) at this site was discovered to be reduced. [20] [21] [22] [23] Abnormal editing is thought to be specific for this condition, as editing levels have not been found to be decreased in spinal and bulbar muscular atrophy. [23] Q/R editing is not the only mechanism involved, as editing occurs only in spinal motor neurons not in upper spinal neurons. Also, it is unknown whether editing dysregulation is involved in the initiation of the condition, or whether it occurs during pathogenesis.

Epilepsy

In mouse models, failure of editing leads to epileptic seizures and death within 3 weeks of birth. [11] Why editing exists at this site instead of a genomically encoded arginine is unknown since nearly 100% of transcripts are edited.

Cancer

Decreased editing at the Q/R site is also found in some human brain tumors. Reduction of ADAR2 expression is thought to be associated with epileptic seizures in malignant glioma. [24]

Use in diagnostic immunochemistry

GRIA2 is a diagnostic immunochemical marker for solitary fibrous tumour (SFT), distinguishing it from most mimics. Among other CD34-positive tumours, GRIA2 is also expressed in dermatofibrosarcoma protuberans (DFSP); however, clinical and histologic features aid in their distinction. GRIA2 shows a limited distribution in other soft tissue tumours. [25]

See also

Related Research Articles

<span class="mw-page-title-main">AMPA receptor</span> Transmembrane protein family

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is an ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core was the first glutamate receptor ion channel domain to be crystallized.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">Kainate receptor</span> Class of ionotropic glutamate receptors

Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.

<span class="mw-page-title-main">Metabotropic glutamate receptor</span> Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

<span class="mw-page-title-main">GRIA3</span> Protein-coding gene in humans

Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.

<span class="mw-page-title-main">Metabotropic glutamate receptor 2</span> Mammalian protein found in humans

Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

<span class="mw-page-title-main">GRIA1</span> Mammalian protein found in Homo sapiens

Glutamate receptor 1 is a protein that in humans is encoded by the GRIA1 gene.

<span class="mw-page-title-main">GRIK2</span> Protein-coding gene in the species Homo sapiens

Glutamate ionotropic receptor kainate type subunit 2, also known as ionotropic glutamate receptor 6 or GluR6, is a protein that in humans is encoded by the GRIK2 gene.

<span class="mw-page-title-main">GRIK1</span> Protein-coding gene in the species Homo sapiens

Glutamate receptor, ionotropic, kainate 1, also known as GRIK1, is a protein that in humans is encoded by the GRIK1 gene.

<span class="mw-page-title-main">GRIA4</span>

Glutamate receptor 4 is a protein that in humans is encoded by the GRIA4 gene.

<span class="mw-page-title-main">GRID2</span> Protein-coding gene in the species Homo sapiens

Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ2, is a protein that in humans is encoded by the GRID2 gene. 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.

<span class="mw-page-title-main">GRIK3</span> Protein-coding gene in the species Homo sapiens

Glutamate receptor, ionotropic kainate 3 is a protein that in humans is encoded by the GRIK3 gene.

<span class="mw-page-title-main">GRIK5</span> Protein-coding gene in the species Homo sapiens

Glutamate receptor, ionotropic kainate 5 is a protein that in humans is encoded by the GRIK5 gene.

<span class="mw-page-title-main">GRID1</span> Protein-coding gene in the species Homo sapiens

Glutamate receptor delta-1 subunit also known as GluD1 or GluRδ1 is a transmembrane protein encoded by the GRID1 gene. A C-terminal GluD1 splicing isoform has been described based on mRNA analysis.

Within the science of molecular biology and cell biology, for human genetics, the GRIA2 gene is located on chromosome 4q32-q33. The gene product is the ionotropic AMPA glutamate receptor 2. The protein belongs to a family of ligand-activated glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA). Glutamate receptors function as the main excitatory neurotransmitter at many synapses in the central nervous system. L-glutamate, an excitatory neurotransmitter, binds to the Gria2 resulting in a conformational change. This leads to the opening of the channel converting the chemical signal to an electrical impulse. AMPA receptors (AMPAR) are composed of four subunits, designated as GluR1 (GRIA1), GluR2 (GRIA2), GluR3 (GRIA3), and GluR4(GRIA4) which combine to form tetramers. They are usually heterotrimeric but can be homodimeric. Each AMPAR has four sites to which an agonist can bind, one for each subunit.[5]

In neuroscience, synaptic scaling is a form of homeostatic plasticity, in which the brain responds to chronically elevated activity in a neural circuit with negative feedback, allowing individual neurons to reduce their overall action potential firing rate. Where Hebbian plasticity mechanisms modify neural synaptic connections selectively, synaptic scaling normalizes all neural synaptic connections by decreasing the strength of each synapse by the same factor, so that the relative synaptic weighting of each synapse is preserved.

Glutamate receptor-interacting protein (GRIP) refers to either a family of proteins that bind to the glutamate receptor or specifically to the GRIP1 protein within this family. Proteins in the glutamate receptor-interacting protein (GRIP) family have been shown to interact with GluR2, a common subunit in the AMPA receptor. This subunit also interacts with other proteins such as protein interacting with C-kinase1 (PICK1) and N-ethylmaleimide-sensitive fusion protein (NSF). Studies have begun to elucidate its function; however, much is still to be learned about these proteins.

<span class="mw-page-title-main">Willardiine</span> Chemical compound

Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See: #Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.

References

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Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.