User:Johno4302/Editing of GluR-6 mRNA

The GRIK2 gene encodes GLUR-6(GRIK2), one of the subunits of the Kainate receptor.Kainate receptors are members of the ionotropic class of glutamate receptors and are composed of four subunits.GluR-6 is one of five subunits that form Kainate receptors.The pre-mRNA of GluR-6 is subjected to RNA Editing.Glutamate receptors mediate fast excitatory neurotransmission in the brain.Huge diversity has been in the  electro- physical properties of these receptors. As well as RNA Splicing, RNA editing of the pre-mRNA of GluR6 is a mechanism that allows ths diversity.

Type of RNA Editing
Adenosine deaminases acting on RNA ( ADARs) are the RNA editing enzymes involved in the editing of GluR-6 mRNA. ADARs deaminate adenosine bases to insosine bases in a site specific manner in double stranded RNA substrates (dsRNA).Editing occurs in the nuclues before splicing occurs.

Editing sites
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 codon (Q) to an arginine codon(R).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. GluR-6 is also edited at I/V and Y/C sites which are found in the first transmembrane domain region.At the I/V site editing results in an amino acid from isoleucine to valine, while at the Y/C site the amino acid change is  from a tyrosine to cysteine.(Kohler et al 1993)The I/V and Y/C editing sites occur within the first transmembrane domain of GluR-6. The RNA fold programme characterised a putative double stranded RNA(dsRNA) conformation around the Q/R site of the GluR-6 pre-mRNA.The possible editing complementary sequence was observed from transcript analysis to be 1.9 kb downstream from the editing site within intron 12.

Editing Regulation
Editing 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% in the adult rat.

Frequency Of Editing
Significant amounts of both edited and non edited 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.

Effects of RNA Editing
The unedited transcript has a glutamine at position 621.This residue determines the low calcium permeability of the channel.In edited transcripts the arginine at this posistion  determines a higher calcium permeability.This is especially true if editing has also occurred at positions  567 and 571 in the TM1 region.This is in contrast to editing at the Q/R position in the other edited  Glu-R as editing usually decreases the permeability of the ion channel. Editing of the Q/R site in GluR-6 pre-mRNA has been demonstrated to be non essential as knock out experiments in mice surive and appear phenotypically normal.Mice lacking the Q/R editing site are capable of NMDA receptor independent long term potentiation but are more susceptible to kainate induced seizures.The number of seizures has been shown to increase with increase in editing at Q/R site.This correlates to humans where the amount of editing increases during seizures and therefore maybe a possible adaptive mechanism. Editing of I/V and Y/C sites are also thought to be involved in permeability of the ion channel.