# GRIA2

## Overview
GRIA2 is a gene that encodes the glutamate ionotropic receptor AMPA type subunit 2 (GluA2), a critical component of AMPA receptors, which are transmembrane receptor channels predominantly expressed in the central nervous system. These receptors play a vital role in fast synaptic transmission and are integral to processes such as learning and memory due to their involvement in synaptic plasticity. The GluA2 subunit, specifically, is essential for determining the ion permeability and voltage rectification properties of AMPA receptors. It undergoes post-transcriptional modifications, notably RNA editing, which are crucial for its function and the biophysical properties of the AMPA receptors. The presence of GluA2 in AMPA receptors affects their calcium permeability and has implications for neuronal excitability and neuroprotection against excitotoxicity (Isaac2007The; Salpietro2019AMPA).

## Structure
The GRIA2 gene encodes the GluA2 subunit of AMPA receptors, which are crucial for synaptic transmission and plasticity in the central nervous system. The molecular structure of the GluA2 protein is complex and includes several key domains essential for its function. The protein structure of GluA2 comprises four main domains: the amino-terminal domain (ATD), the ligand-binding domain (LBD), the transmembrane domain (TMD), and the carboxy-terminal domain (CTD) (Salpietro2019AMPA). 

The LBD is formed by the proximal part of the N terminus (S1 lobe) and the large loop between transmembrane segments M3 and M4 (S2 lobe), which are critical for ligand (glutamate) binding and receptor activation (Salpietro2019AMPA). The TMD consists of hydrophobic membrane-spanning helices M1, M3, and M4, along with the M2 helix and re-entrant loop, which together form the ion-conducting pore (Salpietro2019AMPA). 

Post-transcriptional modifications, particularly RNA editing at the Q/R site at position 607, are significant for the function of the GluA2 subunit. This editing involves a cytosine to guanidine base change, resulting in a glutamine to arginine change, which renders the channel non-rectifying and calcium-impermeable (Salpietro2019AMPA). Additionally, the GluA2 subunits exist in various splice variant isoforms, which can affect the protein's function and interaction with other subunits or ligands (Salpietro2019AMPA).

Overall, the structural and post-translational features of the GluA2 subunit are critical for its role in AMPA receptor function and the regulation of synaptic activity.

## Function
The GRIA2 gene encodes the GluA2 subunit of AMPA receptors, which are tetrameric ligand-gated ion channels essential for fast excitatory neurotransmission in the vertebrate brain. These receptors are predominantly found in the central nervous system and are composed of combinations of GluA1-4 subunits. The presence of the GluA2 subunit in AMPA receptors is crucial for controlling their calcium permeability and voltage rectification properties. This regulation is mediated by an arginine residue in the ion-selectivity filter, which results from the post-transcriptional RNA editing of a codon for glutamine at the Q607 site. This editing process renders heteromultimeric AMPA receptors containing the GluA2 subunit impermeable to calcium ions, thereby establishing a linear relationship between current and trans-membrane voltage (Salpietro2019AMPA).

The GluA2 subunit also plays a significant role in synaptic plasticity, learning, and memory. It is involved in mechanisms such as long-term potentiation and depression, which are thought to underlie information storage and synaptic strength adjustment in the brain (Priya2014Nuclear). Moreover, the GluA2 subunit influences the assembly, trafficking, and synaptic localization of AMPA receptors, impacting neuronal function and protecting neurons from potential excitotoxicity due to excessive calcium influx (Isaac2007The).

## Clinical Significance
Mutations in the GRIA2 gene, which encodes the GluA2 subunit of AMPA receptors, are associated with a range of neurodevelopmental disorders (NDDs) and developmental and epileptic encephalopathies (DEEs). These conditions often manifest as intellectual disability, developmental delay, autism spectrum disorders (ASD), and seizures. The mutations are typically heterozygous and de novo, with significant impacts on synaptic development and plasticity, crucial for cognitive and neurological development (Salpietro2019AMPA).

Specific mutations, such as the A643V and p.A639S variants, have been linked to severe clinical outcomes including epileptic encephalopathy and early death. These mutations affect crucial domains like the ligand-binding domain and the transmembrane domain, impacting the receptor's gating mechanisms and surface trafficking, which are essential for normal receptor operation (Coombs2022A; Salpietro2019AMPA).

Furthermore, novel variants like c.2308G > A (p.Ala770Thr) have been identified in patients with atypical autism and psychiatric symptoms, suggesting a broader spectrum of phenotypes associated with GRIA2 mutations. These variants are often absent from major genomic databases, indicating their rarity and potential high pathogenicity (Cai2022Novel).

Overall, the clinical significance of GRIA2 is underscored by its role in various severe neurological phenotypes, necessitating further research into targeted therapeutic interventions and a deeper understanding of its pathophysiological mechanisms.

## Interactions
GRIA2, encoding the GluA2 subunit of AMPA receptors, interacts with various proteins that regulate its function and localization within neurons. Notably, the RNA-binding protein FUS binds to GRIA2 mRNA within introns and the 3' untranslated region (UTR), playing a crucial role in the splicing and processing of GRIA2 mRNA under normal and stress conditions. This interaction is essential for the nucleocytoplasmic transport of GRIA2 mRNA and its localization in neuronal dendrites during excitotoxic stress induced by glutamate (Tischbein2019The).

In the context of AMPA receptor subtypes, GRIA2 forms part of heterotetrameric complexes with other AMPAR subunits. Specifically, it is involved in forming GluA1/2 and GluA2/3 heterotetramers, prevalent in the hippocampus. These complexes associate with auxiliary proteins such as TARP-γ8, SynDIG4 (Prrt1), and CNIH-2 in the case of GluA1/2, and TARP-γ2, CNIH-2, and Noelin1 (Olfactomedin-1) for GluA2/3 receptors. These interactions are crucial for the differential regulation and functional roles of AMPAR subtypes in synaptic plasticity (van2022Expression).

Additionally, GRIA2 has been identified as a novel interactor in the schizophrenia interactome, targeted by nervous system drugs, suggesting its potential role in neuropsychiatric conditions (Ganapathiraju2016Schizophrenia). These interactions highlight the multifaceted roles of GRIA2 in neuronal function and its implications in various neurological disorders.


## References


[1. (Isaac2007The) John T.R. Isaac, Michael C. Ashby, and Chris J. McBain. The role of the glur2 subunit in ampa receptor function and synaptic plasticity. Neuron, 54(6):859–871, June 2007. URL: http://dx.doi.org/10.1016/j.neuron.2007.06.001, doi:10.1016/j.neuron.2007.06.001. (607 citations) 10.1016/j.neuron.2007.06.001](https://doi.org/10.1016/j.neuron.2007.06.001)

[2. (van2022Expression) Sophie J. F. van der Spek, Nikhil J. Pandya, Frank Koopmans, Iryna Paliukhovich, Roel C. van der Schors, Mylene Otten, August B. Smit, and Ka Wan Li. Expression and interaction proteomics of glua1- and glua3-subunit-containing ampars reveal distinct protein composition. Cells, 11(22):3648, November 2022. URL: http://dx.doi.org/10.3390/cells11223648, doi:10.3390/cells11223648. (6 citations) 10.3390/cells11223648](https://doi.org/10.3390/cells11223648)

[3. (Salpietro2019AMPA) Vincenzo Salpietro, Christine L. Dixon, Hui Guo, Oscar D. Bello, Jana Vandrovcova, Stephanie Efthymiou, Reza Maroofian, Gali Heimer, Lydie Burglen, Stephanie Valence, Erin Torti, Moritz Hacke, Julia Rankin, Huma Tariq, Estelle Colin, Vincent Procaccio, Pasquale Striano, Kshitij Mankad, Andreas Lieb, Sharon Chen, Laura Pisani, Conceicao Bettencourt, Roope Männikkö, Andreea Manole, Alfredo Brusco, Enrico Grosso, Giovanni Battista Ferrero, Judith Armstrong-Moron, Sophie Gueden, Omer Bar-Yosef, Michal Tzadok, Kristin G. Monaghan, Teresa Santiago-Sim, Richard E. Person, Megan T. Cho, Rebecca Willaert, Yongjin Yoo, Jong-Hee Chae, Yingting Quan, Huidan Wu, Tianyun Wang, Raphael A. Bernier, Kun Xia, Alyssa Blesson, Mahim Jain, Mohammad M. Motazacker, Bregje Jaeger, Amy L. Schneider, Katja Boysen, Alison M. Muir, Candace T. Myers, Ralitza H. Gavrilova, Lauren Gunderson, Laura Schultz-Rogers, Eric W. Klee, David Dyment, Matthew Osmond, Mara Parellada, Cloe Llorente, Javier Gonzalez-Peñas, Angel Carracedo, Arie Van Haeringen, Claudia Ruivenkamp, Caroline Nava, Delphine Heron, Rosaria Nardello, Michele Iacomino, Carlo Minetti, Aldo Skabar, Antonella Fabretto, Michael G. Hanna, Enrico Bugiardini, Isabel Hostettler, Benjamin O’Callaghan, Alaa Khan, Andrea Cortese, Emer O’Connor, Wai Y. Yau, Thomas Bourinaris, Rauan Kaiyrzhanov, Viorica Chelban, Monika Madej, Maria C. Diana, Maria S. Vari, Marina Pedemonte, Claudio Bruno, Ganna Balagura, Marcello Scala, Chiara Fiorillo, Lino Nobili, Nancy T. Malintan, Maria N. Zanetti, Shyam S. Krishnakumar, Gabriele Lignani, James E. C. Jepson, Paolo Broda, Simona Baldassari, Pia Rossi, Floriana Fruscione, Francesca Madia, Monica Traverso, Patrizia De-Marco, Belen Pérez-Dueñas, Francina Munell, Yamna Kriouile, Mohamed El-Khorassani, Blagovesta Karashova, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Lionel Van-Maldergem, Wolfgang Nachbauer, Sylvia Boesch, Antonella Gagliano, Elisabetta Amadori, Jatinder S. Goraya, Tipu Sultan, Salman Kirmani, Shahnaz Ibrahim, Farida Jan, Jun Mine, Selina Banu, Pierangelo Veggiotti, Gian V. Zuccotti, Michel D. Ferrari, Arn M. J. Van Den Maagdenberg, Alberto Verrotti, Gian L. Marseglia, Salvatore Savasta, Miguel A. Soler, Carmela Scuderi, Eugenia Borgione, Roberto Chimenz, Eloisa Gitto, Valeria Dipasquale, Alessia Sallemi, Monica Fusco, Caterina Cuppari, Maria C. Cutrupi, Martino Ruggieri, Armando Cama, Valeria Capra, Niccolò E. Mencacci, Richard Boles, Neerja Gupta, Madhulika Kabra, Savvas Papacostas, Eleni Zamba-Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Nuzhat Rana, Osama Atawneh, Shen Y. Lim, Farooq Shaikh, George Koutsis, Marianthi Breza, Domenico A. Coviello, Yves A. Dauvilliers, Issam AlKhawaja, Mariam AlKhawaja, Fuad Al-Mutairi, Tanya Stojkovic, Veronica Ferrucci, Massimo Zollo, Fowzan S. Alkuraya, Maria Kinali, Hamed Sherifa, Hanene Benrhouma, Ilhem B. Y. Turki, Meriem Tazir, Makram Obeid, Sophia Bakhtadze, Nebal W. Saadi, Maha S. Zaki, Chahnez C. Triki, Fabio Benfenati, Stefano Gustincich, Majdi Kara, Vincenzo Belcastro, Nicola Specchio, Giuseppe Capovilla, Ehsan G. Karimiani, Ahmed M. Salih, Njideka U. Okubadejo, Oluwadamilola O. Ojo, Olajumoke O. Oshinaike, Olapeju Oguntunde, Kolawole Wahab, Abiodun H. Bello, Sanni Abubakar, Yahaya Obiabo, Ernest Nwazor, Oluchi Ekenze, Uduak Williams, Alagoma Iyagba, Lolade Taiwo, Morenikeji Komolafe, Konstantin Senkevich, Chingiz Shashkin, Nazira Zharkynbekova, Kairgali Koneyev, Ganieva Manizha, Maksud Isrofilov, Ulviyya Guliyeva, Kamran Salayev, Samson Khachatryan, Salvatore Rossi, Gabriella Silvestri, Nourelhoda Haridy, Luca A. Ramenghi, Georgia Xiromerisiou, Emanuele David, Mhammed Aguennouz, Liana Fidani, Cleanthe Spanaki, Arianna Tucci, Miquel Raspall-Chaure, Michael Chez, Anne Tsai, Emily Fassi, Marwan Shinawi, John N. Constantino, Rita De Zorzi, Sara Fortuna, Fernando Kok, Boris Keren, Dominique Bonneau, Murim Choi, Bruria Benzeev, Federico Zara, Heather C. Mefford, Ingrid E. Scheffer, Jill Clayton-Smith, Alfons Macaya, James E. Rothman, Evan E. Eichler, Dimitri M. Kullmann, and Henry Houlden. Ampa receptor glua2 subunit defects are a cause of neurodevelopmental disorders. Nature Communications, July 2019. URL: http://dx.doi.org/10.1038/s41467-019-10910-w, doi:10.1038/s41467-019-10910-w. (189 citations) 10.1038/s41467-019-10910-w](https://doi.org/10.1038/s41467-019-10910-w)

[4. (Ganapathiraju2016Schizophrenia) Madhavi K Ganapathiraju, Mohamed Thahir, Adam Handen, Saumendra N Sarkar, Robert A Sweet, Vishwajit L Nimgaonkar, Christine E Loscher, Eileen M Bauer, and Srilakshmi Chaparala. Schizophrenia interactome with 504 novel protein–protein interactions. npj Schizophrenia, April 2016. URL: http://dx.doi.org/10.1038/npjschz.2016.12, doi:10.1038/npjschz.2016.12. (68 citations) 10.1038/npjschz.2016.12](https://doi.org/10.1038/npjschz.2016.12)

[5. (Tischbein2019The) Maeve Tischbein, Desiree M. Baron, Yen-Chen Lin, Katherine V. Gall, John E. Landers, Claudia Fallini, and Daryl A. Bosco. The rna-binding protein fus/tls undergoes calcium-mediated nuclear egress during excitotoxic stress and is required for gria2 mrna processing. Journal of Biological Chemistry, 294(26):10194–10210, June 2019. URL: http://dx.doi.org/10.1074/jbc.ra118.005933, doi:10.1074/jbc.ra118.005933. (26 citations) 10.1074/jbc.ra118.005933](https://doi.org/10.1074/jbc.ra118.005933)

[6. (Priya2014Nuclear) Anusha Priya, Kaid Johar, Bindu Nair, and Margaret T.T. Wong-Riley. Nuclear respiratory factor 2 regulates the transcription of ampa receptor subunit glua2 (gria2). Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1843(12):3018–3028, December 2014. URL: http://dx.doi.org/10.1016/j.bbamcr.2014.09.006, doi:10.1016/j.bbamcr.2014.09.006. (14 citations) 10.1016/j.bbamcr.2014.09.006](https://doi.org/10.1016/j.bbamcr.2014.09.006)

[7. (Coombs2022A) A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment (1 citations) 10.1101/2022.03.01.22271646](https://doi.org/10.1101/2022.03.01.22271646)

[8. (Cai2022Novel) Qianyun Cai, Zhongjie Zhou, Rong Luo, Tao Yu, Dengfeng Li, Fan Yang, and Zuozhen Yang. Novel gria2 variant in a patient with atypical autism spectrum disorder and psychiatric symptoms: a case report. BMC Pediatrics, November 2022. URL: http://dx.doi.org/10.1186/s12887-022-03702-7, doi:10.1186/s12887-022-03702-7. (4 citations) 10.1186/s12887-022-03702-7](https://doi.org/10.1186/s12887-022-03702-7)