# GRM2

## Overview
The GRM2 gene is responsible for encoding the metabotropic glutamate receptor 2 (mGluR2), a type of G protein-coupled receptor (GPCR) that plays a crucial role in the central nervous system by modulating neurotransmission and synaptic plasticity. This receptor is primarily activated by glutamate, the main excitatory neurotransmitter in the brain, and functions to inhibit the cyclic AMP (cAMP) pathway, thereby regulating neuronal excitability and synaptic transmission. The protein structure of mGluR2 includes seven transmembrane domains typical of GPCRs, with a significant role in neuroprotective mechanisms and implicated in various neuropsychiatric disorders. The complexity of its function and regulation, including interactions with other neurotransmitter systems, makes mGluR2 a potential target for therapeutic interventions in conditions such as schizophrenia, anxiety, and addiction (Wang2018Metabotropic; Enz2012Metabotropic).

## Structure
The human gene GRM2 encodes the metabotropic glutamate receptor 2 (mGluR2), which is a member of the G protein-coupled receptor (GPCR) family. The molecular structure of mGluR2, like other GPCRs, features seven transmembrane alpha-helices. The extracellular N-terminus of mGluR2 contains the glutamate-binding domain, while the intracellular C-terminus varies in length and is subject to extensive alternative splicing and post-translational modifications such as phosphorylation and SUMOylation (Enz2012Structure; Enz2012Metabotropic).

The intracellular C-terminal domains of mGluR2 are noted for their intrinsically disordered nature, lacking stable secondary or tertiary structures unless interacting with other proteins. This flexibility allows for diverse interactions with various intracellular proteins, influencing receptor signaling and cellular localization (Enz2012Structure). Specific interactions include heterodimerization with the 5-HT 2A receptor through transmembrane domains 4 and 5, mediated by hydrogen bonds and hydrophobic microdomains (Enz2012Metabotropic).

The receptor's ability to form heterodimers and its extensive post-translational modifications contribute to its functional diversity and regulatory complexity, making it a significant target for therapeutic interventions in various neurological disorders.

## Function
The GRM2 gene encodes the metabotropic glutamate receptor 2 (mGluR2), which is a G protein-coupled receptor (GPCR) involved in modulating neurotransmission and synaptic plasticity in the central nervous system (CNS). mGluR2 is primarily activated by the neurotransmitter L-glutamate, the predominant excitatory neurotransmitter in the CNS. Upon activation, mGluR2 inhibits the production of cyclic AMP (cAMP) by suppressing the activity of adenylyl cyclase. This inhibition is crucial for regulating excitatory neurotransmission and maintaining synaptic plasticity, which are essential for learning and memory (Wang2018Metabotropic; Joo2001Structure).

In terms of cellular function, mGluR2 is involved in mediating fast synaptic responses and plays a significant role in neuroprotective mechanisms against excitotoxicity, which is critical in conditions like cerebral ischemia and epilepsy. The receptor's activity modulates various intracellular signal transduction pathways, influencing neuronal survival and function (Wang2018Metabotropic; Lee2009The).

Additionally, mGluR2 has been implicated in the pathogenesis of several neuropsychiatric disorders, including schizophrenia, anxiety, and drug addiction. Its modulation of glutamate neurotransmission and interaction with other neurotransmitter systems, such as the dopaminergic system, underlines its potential as a therapeutic target in these conditions (Martí2001Human; Joo2001Structure).

## Clinical Significance
Mutations in the GRM2 gene, which encodes the metabotropic glutamate receptor 2 (mGlu2), have been linked to various behavioral and psychiatric conditions. Notably, a specific mutation involving a premature stop codon at cysteine 407 (cys407*) results in the loss of functional mGlu2 receptor expression. This mutation has been extensively studied in animal models, particularly in Hannover-derived Wistar rats, where it is associated with increased alcohol intake, risk-taking behaviors, and emotional disturbances (Wood2017Prevalence). These findings suggest a potential role of GRM2 in modulating behaviors related to substance abuse and emotional regulation.

In human studies, the association of GRM2 with psychiatric disorders has been explored, particularly in the context of methamphetamine-induced psychosis and schizophrenia. While some studies have found a significant association between GRM2 and methamphetamine-induced psychosis, indicating a potential role in the pathophysiology of this condition (Tsunoka2010Association), other studies have not found a significant association with schizophrenia (Maj2016The; Joo2001Structure). These mixed results highlight the complexity of GRM2's role in human psychiatric conditions and underscore the need for further research to clarify its clinical significance.

## Interactions
GRM2, encoding the glutamate metabotropic receptor 2, is involved in several protein-protein interactions that are crucial for its function in modulating neurotransmission. The receptor primarily functions as an inhibitory autoreceptor and heteroreceptor, modulating the release of neurotransmitters such as dopamine and GABA through interactions with G-proteins that inhibit adenylate cyclase and decrease cAMP formation (Lyon2008Altered). Additionally, interactions between GRM2 and other group II metabotropic glutamate receptors, specifically GRM3, have been observed. Studies using knockout mice have shown that the absence of GRM3 leads to compensatory increases in GRM2 mRNA levels, suggesting a regulatory interplay between these receptors (Lyon2008Altered). Furthermore, the interactions of GRM2 with NMDA receptor subunits have been implicated, with changes in the expression of these receptors observed in the hippocampus of knockout mice, indicating a complex network of receptor interactions influencing glutamatergic signaling (Lyon2008Altered).

These interactions are essential for the physiological role of GRM2 in the central nervous system, influencing synaptic plasticity and neuronal excitability, and have implications for understanding the molecular mechanisms underlying various neurological disorders.


## References


[1. (Wood2017Prevalence) Christian M. Wood, Celine S. Nicolas, Sun-Lim Choi, Erika Roman, Ingrid Nylander, Alberto Fernandez-Teruel, Kalervo Kiianmaa, Przemyslaw Bienkowski, Trynke R. de Jong, Giancarlo Colombo, Denis Chastagnier, Keith A. Wafford, Graham L. Collingridge, Sheryl J. Wildt, Becky L. Conway-Campbell, Emma S.J. Robinson, and David Lodge. Prevalence and influence of cys407* grm2 mutation in hannover-derived wistar rats: mglu2 receptor loss links to alcohol intake, risk taking and emotional behaviour. Neuropharmacology, 115:128–138, March 2017. URL: http://dx.doi.org/10.1016/j.neuropharm.2016.03.020, doi:10.1016/j.neuropharm.2016.03.020. (44 citations) 10.1016/j.neuropharm.2016.03.020](https://doi.org/10.1016/j.neuropharm.2016.03.020)

[2. (Wang2018Metabotropic) Jinliang Wang, Zilong Wang, Renqiang Liu, Lei Shuai, Xinxin Wang, Jie Luo, Chong Wang, Weiye Chen, Xijun Wang, Jinying Ge, Xijun He, Zhiyuan Wen, and Zhigao Bu. Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus. PLOS Pathogens, 14(7):e1007189, July 2018. URL: http://dx.doi.org/10.1371/journal.ppat.1007189, doi:10.1371/journal.ppat.1007189. (89 citations) 10.1371/journal.ppat.1007189](https://doi.org/10.1371/journal.ppat.1007189)

[3. (Maj2016The) Carlo Maj, Alessandra Minelli, Edoardo Giacopuzzi, Emilio Sacchetti, and Massimo Gennarelli. The role of metabotropic glutamate receptor genes in schizophrenia. Current Neuropharmacology, 14(5):540–550, June 2016. URL: http://dx.doi.org/10.2174/1570159x13666150514232745, doi:10.2174/1570159x13666150514232745. (20 citations) 10.2174/1570159x13666150514232745](https://doi.org/10.2174/1570159x13666150514232745)

[4. (Enz2012Structure) Ralf Enz. Structure of metabotropic glutamate receptor c-terminal domains in contact with interacting proteins. Frontiers in Molecular Neuroscience, 2012. URL: http://dx.doi.org/10.3389/fnmol.2012.00052, doi:10.3389/fnmol.2012.00052. (47 citations) 10.3389/fnmol.2012.00052](https://doi.org/10.3389/fnmol.2012.00052)

[5. (Enz2012Metabotropic) Ralf Enz. Metabotropic glutamate receptors and interacting proteins: evolving drug targets. Current Drug Targets, 13(1):145–156, January 2012. URL: http://dx.doi.org/10.2174/138945012798868452, doi:10.2174/138945012798868452. (69 citations) 10.2174/138945012798868452](https://doi.org/10.2174/138945012798868452)

[6. (Martí2001Human) Sylvia Bort Martí, Sven Cichon, Peter Propping, and Markus Nöthen. Human metabotropic glutamate receptor 2 gene (grm2): chromosomal sublocalization (3p21.1–p21.2) and genomic organization. American Journal of Medical Genetics, 114(1):12–14, November 2001. URL: http://dx.doi.org/10.1002/ajmg.1622, doi:10.1002/ajmg.1622. (14 citations) 10.1002/ajmg.1622](https://doi.org/10.1002/ajmg.1622)

[7. (Joo2001Structure) A Joo, H Shibata, H Ninomiya, H Kawasaki, N Tashiro, and Y Fukumaki. Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (grm2): analysis of association with schizophrenia. Molecular Psychiatry, 6(2):186–192, March 2001. URL: http://dx.doi.org/10.1038/sj.mp.4000841, doi:10.1038/sj.mp.4000841. (51 citations) 10.1038/sj.mp.4000841](https://doi.org/10.1038/sj.mp.4000841)

[8. (Lee2009The) Hyoung-gon Lee, Xiongwei Zhu, Gemma Casadesus, Mercé Pallàs, Antoni Camins, Michael J. O’Neill, Shigetada Nakanishi, George Perry, and Mark A. Smith. The effect of mglur2 activation on signal transduction pathways and neuronal cell survival. Brain Research, 1249:244–250, January 2009. URL: http://dx.doi.org/10.1016/j.brainres.2008.10.055, doi:10.1016/j.brainres.2008.10.055. (48 citations) 10.1016/j.brainres.2008.10.055](https://doi.org/10.1016/j.brainres.2008.10.055)

[9. (Tsunoka2010Association) Tomoko Tsunoka, Taro Kishi, Tsuyoshi Kitajima, Tomo Okochi, Takenori Okumura, Yoshio Yamanouchi, Yoko Kinoshita, Kunihiro Kawashima, Hiroshi Naitoh, Toshiya Inada, Hiroshi Ujike, Mitsuhiko Yamada, Naohisa Uchimura, Ichiro Sora, Masaomi Iyo, Norio Ozaki, and Nakao Iwata. Association analysis of grm2 and htr2a with methamphetamine-induced psychosis and schizophrenia in the japanese population. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34(4):639–644, May 2010. URL: http://dx.doi.org/10.1016/j.pnpbp.2010.03.002, doi:10.1016/j.pnpbp.2010.03.002. (34 citations) 10.1016/j.pnpbp.2010.03.002](https://doi.org/10.1016/j.pnpbp.2010.03.002)

[10. (Lyon2008Altered) Louisa Lyon, James N.C. Kew, Corrado Corti, Paul J. Harrison, and Philip W.J. Burnet. Altered hippocampal expression of glutamate receptors and transporters in grm2 and grm3 knockout mice. Synapse, 62(11):842–850, August 2008. URL: http://dx.doi.org/10.1002/syn.20553, doi:10.1002/syn.20553. (65 citations) 10.1002/syn.20553](https://doi.org/10.1002/syn.20553)