Glutamate ionotropic receptor kainate type subunit 2, also known as ionotropic glutamate receptor 6 or GluR6, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''GRIK2'' (or ''GLUR6'')
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
Function
This gene encodes a subunit of a
kainate glutamate receptor. This receptor may have a role in synaptic plasticity, learning, and memory. It also may be involved in the transmission of visual information from the retina to the hypothalamus. The structure and function of the encoded protein is influenced by
RNA editing
RNA editing (also RNA modification) is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organism ...
. Alternatively spliced transcript variants encoding distinct isoforms have been described for this gene.
Clinical significance
Homozygosity for a GRIK2 deletion-inversion mutation is associated with non-syndromic autosomal recessive mental retardation.
Interactions
GRIK2 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
DLG1
Discs large homolog 1 (DLG1), also known as synapse-associated protein 97 or SAP97, is a scaffold protein that in humans is encoded by the ''SAP97'' gene.
SAP97 is a mammalian MAGUK-family member protein that is similar to the Drosophila protein ...
,
[
* DLG4,]
* 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. This protein together with GRID1, GluD1 belongs to the delta receptor subtype of ionotropic glutamate rec ...
,
* GRIK5
Glutamate receptor, ionotropic kainate 5 is a protein that in humans is encoded by the ''GRIK5'' gene.
Function
This gene encodes a protein that belongs to the glutamate-gated ionic channel family. Glutamate functions as the major excitatory ...
,
* GRIP1,
* PICK1
Protein Interacting with C Kinase - 1 is a protein that in humans is encoded by the ''PICK1'' gene.
Function
The protein encoded by this gene contains a PDZ domain, through which it interacts with protein kinase C, alpha ( PRKCA). This protein ...
[ and
* ]SDCBP
Syntenin-1 is a protein that in humans is encoded by the ''SDCBP'' gene.
Function
The protein encoded by this gene was initially identified as a molecule linking syndecan-mediated signaling to the cytoskeleton. The syntenin protein contains ta ...
.[
]
RNA Editing
Pre-mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
for several neurotransmitter receptors and ion channels are substrates for ADAR
Adar ( he, אֲדָר ; from Akkadian ''adaru'') is the sixth month of the civil year and the twelfth month of the religious year on the Hebrew calendar, roughly corresponding to the month of March in the Gregorian calendar. It is a month of 29 d ...
s, including AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic transmembrane receptor for glutamate (iGluR) that mediates fast synapse, synap ...
subunits ( GluR2, GluR3
Glutamate receptor 3 is a protein that in humans is encoded by the ''GRIA3'' gene.
Function
Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophys ...
, GluR4) and kainate receptor
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 dru ...
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 similar to that found in K+ channels (e.g. the human Kv1.1 channel, whose pre-mRNA is also subject to A to I RNA editing). The diversity of ionotropic glutamate receptor
Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate. They mediate the majority of excitatory synaptic transmission throughout the central nervous system and are key players in ...
subunits, as well as RNA splicing, is determined by RNA editing events of the individual subunits, explaining their extremely high diversity.
Type
The type of RNA editing that occurs in the pre-mRNA
A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs a ...
of GluR6 is Adenosine to Inosine (A to I) editing.
[52. Seeburg PH, Higuchi M, Sprengel R. Brain Res Brain Res Rev. 1998;26:217–29.]
A to I RNA editing is catalyzed by a family of adenosine deaminase
Adenosine deaminase (also known as adenosine aminohydrolase, or ADA) 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.
Its primary function ...
s acting on RNA (ADARs) that specifically recognize adenosines within double-stranded regions of pre-mRNAs and deaminate them to inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9-glycosidic bond. It was discovered in 1965 in analysis of RNA transferase.
Inosine is commonly found in tRNAs and is e ...
. Inosine
Inosine is a nucleoside that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9-glycosidic bond. It was discovered in 1965 in analysis of RNA transferase.
Inosine is commonly found in tRNAs and is e ...
s are recognised as guanosine
Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose (ribofuranose) ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate (c ...
by the cell's translational machinery. There are three members of the ADAR family ADARs 1-3 with ADAR1 and ADAR2 being the only enzymatically-active members. ADAR1 and ADAR2 are widely expressed in tissues, while ADAR3 is restricted to the brain, where it is though tot have a regulatory role. The double-stranded regions of RNA are formed by base-pairing between residues close to region of the editing site, with residues usually in a neighboring intron
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
, though they can occasionally be located in an exonic
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
sequence. The region that forms 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
In molecular genetics, an untranslated region (or UTR) refers to either of two sections, one on each side of a coding sequence on a strand of mRNA. If it is found on the 5' side, it is called the 5' UTR (or leader sequence), or if it is foun ...
(UTRs), LINEs
Line most often refers to:
* Line (geometry), object with zero thickness and curvature that stretches to infinity
* Telephone line, a single-user circuit on a telephone communication system
Line, lines, The Line, or LINE may also refer to:
Arts ...
, and SINEs
Sines () is a city and a municipality in Portugal. The municipality, divided into two parishes, has around 14,214 inhabitants (2021) in an area of . Sines holds an important oil refinery and several petrochemical industries. It is also a popular ...
(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
A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs a ...
of GLUR6 is edited at amino acid positions 567, 571, and 621.
The Q/R position, which gets its name as editing results in an codon change from a glutamine (Q) codon (CAG) to an arginine (R) codon (CGG), is located in the "pore loop" of the second membrane domain (M2). The Q/R site of GluR6 pre-mRNA occurs in an asymmetrical loop of three exonic and four intronic nucleotides. The Q/R editing site is also observed in GluR2 and GluR5. The Q/R site is located in a homologous position in GluR2 and in GluR6.
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 RNAfold program 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 GluR6 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 the AMPA receptor subunit GluR2, which is nearly 100% edited and is not developmentally regulated.
Significant amounts of both edited and non-edited forms of GluR6 transcripts are found in the adult brain. The receptor is 90% edited in all grey matter structures, while in white matter, the receptor is edited in just 10% of cases.
Frequency increases from 0% in rat embryo to 85% in adult rat.
Consequences
Structure
The primary GluR6 transcripts can be edited in up to three positions. Editing at each of the three positions affects 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 GluR6. It has been reported that the unedited version of GluR6 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 exhibit increased long term potentiation and are more susceptible to kainate induced seizures. The number of seizures is inversely correlated with the amount of RNA editing. Human GluR6 pre-mRNA editing is increased during seizures, possibly as an adaptive mechanism.
Up to 8 different protein isoforms can occur as a result of different combinations of editing at the three sites, giving rise to receptor variants with differing kinetics. The effect of Q/R site editing on calcium permeability appears to be dependent on editing of the I/V and Y/C sites. When both sites in TM1 (I/V and Y/C) are edited, Q/R site editing is required for calcium permeability. On the contrary, when neither the I/V nor the Y/C site is edited, receptors demonstrate high calcium permeability regardless of Q/R site editing. The co-assembly of these two isoforms generate receptors with reduced calcium permeability.
RNA editing of the Q/R site can affect inhibition of the channel by membrane fatty acids such as arachidonic acid and docosahexaenoic acid
Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. In physiological literature, it is given the name 22:6(n-3). It can be synthesized from alpha-lino ...
For Kainate receptors with only edited isforms, these are strongly inhibited by these fatty acids, however inclusion of just one non-edited subunit is enough to abolish this effect.
Dysregulation
Kainate-induced seizures in mice are used as a model of temporal lobe epilepsy in humans. Despite mice deficient in editing at the Q/R site of GluR6 showing increased seizure susceptibility, tissue analysis of human epilepsy patients did not show reduced editing at this site.
See also
* Kainate receptor
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 dru ...
References
Further reading
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External links
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{{Ligand-gated ion channels
Ionotropic glutamate receptors