GRIK2
Encyclopedia
Glutamate receptor, ionotropic kainate 2 is a protein
that in humans is encoded by the GRIK2 gene
.
with DLG4
, GRID2
, GRIP1
, DLG1
, GRIK5
, PICK1
and SDCBP
.
as substrates for ADAR
s. 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). The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing. 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 GRIK2 gene is subject to RNA editing.
A to I RNA editing is catalyzed by a family of adenosine deaminase
s acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine
. Inosine
s 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, the result could be 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 noncoding 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.
The Q/R posistion is so called as editing results in an codon change from a glutamine (Q) codon (CAG ) to an arginine (R) codon (CGG). This editing site is located in the " pore loop" of the second membrane domain (M2). Q/R editing site is also observed in glutamte recptor GluR-2 and GluR-5. The Q/R site of GluR-6 pre mRNA occurs in an asymmetrical loop of 3 exonic and four intronic nucleotides. The Q/R site is located in a homologous position in GluR-2 and in GluR-6.
GluR-6 is also edited at I/V and Y/C sites, which are found in the first membrane domain (M1). At the I/V site editing results in a codon change from (ATT) isoleucine (I) to (GTT)valine (V), while at the Y/C site the codon change is from (TAC) tyrosine(Y) to (TGC) cysteine (C).
The RNA fold programme characterised a putative double-stranded RNA(dsRNA) conformation around the Q/R site of the GluR-6 pre-mRNA. This sequence is necessary for editing at the site to occur. The possible editing complementary sequence was observed from transcript analysis to be 1.9 kb downstream from the editing site within intron 12.
The ECS for the editing sites in M1 has yet to be identified but it is likely to occur at a considerable distance from the editing sites.
Significant amounts of both edited and nonedited forms of GluR-6 transcripts are found in adult brain. The receptor is 90% edited in all grey matter structures. In white matter of the brain the receptor is in edited form in just 10% of cases.
Frequency increases from 0% in rat embryo to 85% in adult rat.
The primary of GluR-6 transcripts can be edited in up to three positions. Editing at each of the 3 positions have an impact on the Ca2+ permeability of the channel
Editing plays a role in the electrophysiology of the channel.
Editing at the Q/R site has been deemed to be nonessential in GluR-6. It has been reported that unedited version of Glu-R6 functions in the regulation of synaptic plasticity. The edited version is thought to inhibit synaptic plasticity and reduce seizure susceptibility.
Mice lacking the Q/R site are capable of long term potentiation and are more susceptible to kainate induced seizures. The number of seizures inversely correlates with the amount of rna editing. This correlates to the increase in human GluR-6 pre-mRNA editing during seizures. It is thought that editing maybe an adaptive mechanism.
Up to 8 different protein isoforms can occur as a result of different combinations of editing at the three sites.
Editing at the Q/R site effects the calcium permeabilty of the receptor. The two other editing sites are less well defined (I/V,Y/C) but are also thought to be involved in regulation of calcium permeability.(59) Evidence suggests that if editing does not occur at I/V and Y/C sites
then both edited and nonedited versions of the receptor demonstrate high calcium permeability. When both editing sites in TM1 are edited then the Q/R site edited version of the receptor is more permeable to calcium than the nonedited version at the Q/R site. The co assembly of these two isoforms generate receptor with reduced calcium permeability.
Rna editing of the Q/R site can effect inhibition of the channel by membrane fatty acids such as arachidonic acid
and docosahexaenoic acid
For Kainate receptors with only edited isforms, these are strongly inhibited by these fatty acids.However inclusion of just one nonedited subunit is enough to stop this inhibition(.
Kainate induced seizures in mice are used as a model of temporal lobe epilepsy in humans. Despite deficency in editing at the Q/R site of GluR-6 in mice increasing seizure vulnerability , tissue analysis of human patients did not show reduced editing at this site.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the GRIK2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Clinical significance
Homozygosity for a GRIK2 deletion-inversion mutation is associated with nonsyndromic autosomal recessive mental retardation.Interactions
GRIK2 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with DLG4
DLG4
PSD-95 also known as SAP-90 is a protein that in humans is encoded by the DLG4 gene....
, GRID2
GRID2
Glutamate receptor, ionotropic, delta 2, also known as GluD2, GluRδ2, or δ2, is a protein that in humans is encoded by the GRID2 gene....
, GRIP1
GRIP1 (gene)
Glutamate receptor-interacting protein 1 is a protein that in humans is encoded by the GRIP1 gene.-Interactions:GRIP1 has been shown to interact with GRIA4, Metabotropic glutamate receptor 3, GRIK2, GRIK3, GRIPAP1, GRIA2 and GRIA3....
, DLG1
DLG1
Disks large homolog 1 , also known as synapse-associated protein 97 or SAP97, is a protein that in humans is encoded by the SAP97 gene....
, GRIK5
GRIK5
Glutamate receptor, ionotropic kainate 5 is a protein that in humans is encoded by the GRIK5 gene.-Interactions:GRIK5 has been shown to interact with DLG4 and GRIK2....
, PICK1
PICK1
PRKCA-binding protein is a protein that in humans is encoded by the PICK1 gene.-Interactions:PICK1 has been shown to interact with HER2/neu, ACCN2, Metabotropic glutamate receptor 7, BNC1, Metabotropic glutamate receptor 3, GRIA4, Dopamine transporter, GRIK1, GRIK2, GRIK3, GRIA2 and GRIA3.-Further...
and SDCBP
SDCBP
Syntenin-1 is a protein that in humans is encoded by the SDCBP gene.-Interactions:SDCBP has been shown to interact with Merlin, ULK1, Interleukin 5 receptor alpha subunit, SOX4, RAB5A, EFNB1, TRAF6, GRIK1 and GRIK2.-Further reading:...
.
RNA Editing
Several ion channels and neurotransmitters receptors pre-mRNAMessenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
as substrates for ADAR
ADAR
Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene.-Further reading:...
s. This includes 5 subunits of the glutamate receptor ionotropic AMPA glutamate receptor subunits (Glur2
Metabotropic glutamate receptor 2
Metabotropic glutamate receptor 2 is a protein that in humans is encoded by the GRM2 gene.-PAMs:The development of subtype-2-selective positive allosteric modulators experienced steady advance in recent years...
, Glur3
Metabotropic glutamate receptor 3
Metabotropic glutamate receptor 3 is a protein that in humans is encoded by the GRM3 gene.-Ligands:Though truly mGluR3 selective agents still await their discovery, mixed mGluR2/3 ligands with selectivity over other mGluR-subtypes are known...
, Glur4
Metabotropic glutamate receptor 4
Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene.Together with GRM6, GRM7 and GRM8 it belongs to group III of the metabotropic glutamate receptor family. Group III receptors are linked to the inhibition of the cyclic AMP cascade.Activation of GRM4 has...
) and kainate receptor
Kainate receptor
Kainate receptors, or KARs, are non-NMDA ionotropic receptors which 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 red algae Digenea simplex. KARs are less well...
subunits (Glur5
Metabotropic glutamate receptor 5
Metabotropic glutamate receptor 5 is a protein that in humans is encoded by the GRM5 gene.- Function :The amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors...
, Glur6
Metabotropic glutamate receptor 6
Glutamate receptor, metabotropic 6, also known as GRM6, is a protein which in humans is encoded by the GRM6 gene.- Function :L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors...
). 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). The human Kv1.1 channel pre mRNA is also subject to A to I RNA editing. 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 GRIK2 gene is subject to RNA editing.
Type
The type of RNA editing that occurs in the pre-mRNA of GluR-6 is Adenosine to Inosine ( A to I) editing.A to I RNA editing is catalyzed by a family of adenosine deaminase
Adenosine deaminase
Adenosine deaminase is an enzyme involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.-Reactions:...
s acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
. Inosine
Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring via a β-N9-glycosidic bond....
s are recognised as guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
by the cells translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1
ADAR
Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene.-Further reading:...
and ADAR2
ADARB1
Double-stranded RNA-specific editase 1 is an enzyme that in humans is encoded by the ADARB1 gene.ADAR2 requires the small molecule inositol hexakisphosphate for proper function.-Further reading:...
being the only enzymatically active members. ADAR3
ADARB2
Double-stranded RNA-specific editase B2 is an enzyme that in humans is encoded by the ADARB2 gene.-Further reading:...
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, the result could be 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 noncoding 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
The pre-mRNA of GLUR-6 is edited at three positions at amino acid positions 567 , 571, and 621.The Q/R posistion is so called as editing results in an codon change from a glutamine (Q) codon (CAG ) to an arginine (R) codon (CGG). This editing site is located in the " pore loop" of the second membrane domain (M2). Q/R editing site is also observed in glutamte recptor GluR-2 and GluR-5. The Q/R site of GluR-6 pre mRNA occurs in an asymmetrical loop of 3 exonic and four intronic nucleotides. The Q/R site is located in a homologous position in GluR-2 and in GluR-6.
GluR-6 is also edited at I/V and Y/C sites, which are found in the first membrane domain (M1). At the I/V site editing results in a codon change from (ATT) isoleucine (I) to (GTT)valine (V), while at the Y/C site the codon change is from (TAC) tyrosine(Y) to (TGC) cysteine (C).
The RNA fold programme characterised a putative double-stranded RNA(dsRNA) conformation around the Q/R site of the GluR-6 pre-mRNA. This sequence is necessary for editing at the site to occur. The possible editing complementary sequence was observed from transcript analysis to be 1.9 kb downstream from the editing site within intron 12.
The ECS for the editing sites in M1 has yet to be identified but it is likely to occur at a considerable distance from the editing sites.
Regulation
Editing of the Q/R site in GluR-6 pre-mRNA has been demonstrated to be developmentally regulated in rats ranging from 0% in rat embryo to 80% at birth. This is different from AMPA receptor subunit GluR-B, which is edited nearly 100% and is not developmentally regulated.Significant amounts of both edited and nonedited forms of GluR-6 transcripts are found in adult brain. The receptor is 90% edited in all grey matter structures. In white matter of the brain the receptor is in edited form in just 10% of cases.
Frequency increases from 0% in rat embryo to 85% in adult rat.
Structure
The primary of GluR-6 transcripts can be edited in up to three positions. Editing at each of the 3 positions have an impact on the Ca2+ permeability of the channel
Function
Editing plays a role in the electrophysiology of the channel.
Editing at the Q/R site has been deemed to be nonessential in GluR-6. It has been reported that unedited version of Glu-R6 functions in the regulation of synaptic plasticity. The edited version is thought to inhibit synaptic plasticity and reduce seizure susceptibility.
Mice lacking the Q/R site are capable of long term potentiation and are more susceptible to kainate induced seizures. The number of seizures inversely correlates with the amount of rna editing. This correlates to the increase in human GluR-6 pre-mRNA editing during seizures. It is thought that editing maybe an adaptive mechanism.
Up to 8 different protein isoforms can occur as a result of different combinations of editing at the three sites.
Editing at the Q/R site effects the calcium permeabilty of the receptor. The two other editing sites are less well defined (I/V,Y/C) but are also thought to be involved in regulation of calcium permeability.(59) Evidence suggests that if editing does not occur at I/V and Y/C sites
then both edited and nonedited versions of the receptor demonstrate high calcium permeability. When both editing sites in TM1 are edited then the Q/R site edited version of the receptor is more permeable to calcium than the nonedited version at the Q/R site. The co assembly of these two isoforms generate receptor with reduced calcium permeability.
Rna editing of the Q/R site can effect inhibition of the channel by membrane fatty acids such as arachidonic acid
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...
and docosahexaenoic acid
Docosahexaenoic acid
Docosahexaenoic acid is an omega-3 fatty acid that is a primary structural component of the human brain and retina. In chemical structure, DHA is a carboxylic acid with a 22-carbon chain and six cis double bonds; the first double bond is located at the third carbon from the omega end...
For Kainate receptors with only edited isforms, these are strongly inhibited by these fatty acids.However inclusion of just one nonedited subunit is enough to stop this inhibition(.
Dysregulation
Kainate induced seizures in mice are used as a model of temporal lobe epilepsy in humans. Despite deficency in editing at the Q/R site of GluR-6 in mice increasing seizure vulnerability , tissue analysis of human patients did not show reduced editing at this site.