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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 ( also known as Glur2 or GlurB). 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 (such as L-glutamate) can bind, one for each subunit.
RNA editing
Editing type
Gria2 pre-mRNA undergoes a type of editing called adenosine-to-inosine (A-to-I) editing. Adenosine deaminases acting on RNA (ADARs) are the RNA editing enzymes responsible for A-to-I editing. ADARs deaminate adenosine bases to inosine bases in a site-specific manner in double-stranded RNA substrates (dsRNA). ADAR2 has been experimentally shown to be the specifically responsible
Editing site
The pre-mRNA of GRIA2 is modified at amino acid 607, found in the second transmembrane domain of the receptor subunit. This is called the Q/R site.
Editing regulation
Editing occurs in 100% of transcripts in human brain. Editing levels are lower in other tissues. Deletion analysis determined that editing requires 5' portion of intron B. The predicted minimum fragment required for editing to occur contains inverted repeat structure separated by 120 nucleotides. The inverted repeat contains 3 double stranded elements of 22-23 base pairs with distortion after 15-17 base pairs with mismatched pairs in helical structure 1 and 3 and a bulge in helical structure 2.
Effects of Rna editing
Protein structure
The genomically encoded GluR2 subunit has a Gln (CAG) at the editing site position. Editing of the pre-mRNA results in conversion to Arg (CGG) being encoded at this position.
Protein function
Editing alters Ca2+ permeability.
Dysfunctional editing
GluA2 RNA editing has recently been described to be dysregualted in Alzheimer's disease and the latest research has shown that modulating RNA editing can lead to functional benefits in an Alzheimer mouse model
Thiamine (Vitamin B1) deficiency
Deficiency of vitamin B1 is correlated with alterations in editing of Glur2 pre-mRNA. Thiamine deficiency leads to mild impairment of oxidative metabolism and regional selective neuronal loss in the central nervous system. An increase in intracellular calcium has been experimentally observed in cultured cortical neurons as a result of lack of thiamine. Deficiency also inhibits editing of the Q/R site of Glur2 thereby increasing the level of unedited Glur2 resulting in increased calcium permeability of Glur2 containing channels.
References
- "GRIA2 Gene - GeneCards | GRIA2 Protein | GRIA2 Antibody".
- Stefl R, Oberstrass FC, Hood JL, Jourdan M, Zimmermann M, Skrisovska L, Maris C, Peng L, Hofr C, Emeson RB, Allain FHT. The solution structure of the ADAR2 dsRBM-RNA complex reveals a sequence specific readout of the minor groove. Cell 2010;143 (2):225–237.
- Egebjerg, J., Kukekov, V., Heinemann, S. F. (1994) Proceedings of the National Academy of Sciences of the United States of America, 91, 10270-10274.
- Sommer, B., Kohler, M., Sprengel, R. & Seeburg, P. H. (1991) Cell 67, 11-20
- Wright, Amanda L.; Konen, Lyndsey M.; Mockett, Bruce G.; Morris, Gary P.; Singh, Anurag; Burbano, Lisseth Estefania; Milham, Luke; Hoang, Monica; Zinn, Raphael; Chesworth, Rose; Tan, Richard P.; Royle, Gordon A.; Clark, Ian; Petrou, Steven; Abraham, Wickliffe C.; Vissel, Bryce (28 September 2023). "The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer's disease". Molecular Neurodegeneration. 18 (1): 65. doi:10.1186/s13024-023-00632-5. PMC 10537207. PMID 37759260.
- Lee, Shuchen; Yang, Guang; Yong, Yue; Liu, Ying; Zhao, Liyun; Xu, Jing; Zhang, Xiaomin; Wan, Yanjie; Feng, Chun (2010-11-27). "ADAR2-dependent RNA editing of GluR2 is involved in thiamine deficiency-induced alteration of calcium dynamics". Molecular Neurodegeneration. 5: 54. doi:10.1186/1750-1326-5-54. ISSN 1750-1326. PMC 3006372. PMID 21110885.