Grm4, also known as metabotropic glutamate receptor 4, is a crucial receptor within the glutamate-related signaling system. Glutamate is a major excitatory neurotransmitter in the central nervous system, and Grm4 is involved in regulating glutamatergic synapse pathways, which are important for normal neural function [1]. It has been implicated in various biological processes and diseases, highlighting its overall biological importance. Genetic models, such as knockout (KO) mouse models, can be valuable in studying its functions.

In osteosarcoma, Grm4 -/- gene-targeted mice show accelerated radiation-induced tumor development, comparable to Rb1+/- mice, indicating its role in suppressing osteosarcoma development [3]. In breast cancer, overexpression of Grm4 inhibits cell proliferation, migration, and invasion, suggesting it may act as a tumor suppressor gene [4]. In glioma, low expression of Grm4 is associated with poor prognosis and is related to tumor immune infiltration [2]. Also, in epilepsy studies, association analysis of GRM4 SNPs in IGE patients shows a possible low-risk contribution of GRM4 sequence variants to the etiology of IGE [5].

In conclusion, Grm4 plays essential roles in multiple biological processes, especially in tumor-related and neurological disease conditions. The use of Grm4 KO mouse models and genetic association studies has revealed its functions in suppressing osteosarcoma, breast cancer cell malignancy, and its potential role in epilepsy etiology. These findings provide valuable insights into the underlying mechanisms of these diseases and potential therapeutic targets related to Grm4.

References:

1. Jones, Sara K, McCarthy, Deirdre M, Vied, Cynthia, Schatschneider, Chris, Bhide, Pradeep G. 2022. Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala. In Proceedings of the National Academy of Sciences of the United States of America, 119, e2213120119. doi:10.1073/pnas.2213120119. https://pubmed.ncbi.nlm.nih.gov/36459641/

2. Fan, Hai, Yan, Dongming, Fang, Xingyue, Geng, Dangmurenjiafu, Liu, Qibing. 2024. Low expression of GRM4 is associated with poor prognosis and tumor immune infiltration in glioma. In The International journal of neuroscience, 134, 1674-1686. doi:10.1080/00207454.2023.2297646. https://pubmed.ncbi.nlm.nih.gov/38164693/

3. Kansara, Maya, Thomson, Kristian, Pang, Puiyi, Smyth, Mark J, Thomas, David M. 2019. Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23. In Cancer discovery, 9, 1511-1519. doi:10.1158/2159-8290.CD-19-0154. https://pubmed.ncbi.nlm.nih.gov/31527131/

4. Xiao, Bin, Chen, Daxiang, Zhou, Quan, Sun, Zhaohui, Li, Linhai. 2019. Glutamate metabotropic receptor 4 (GRM4) inhibits cell proliferation, migration and invasion in breast cancer and is regulated by miR-328-3p and miR-370-3p. In BMC cancer, 19, 891. doi:10.1186/s12885-019-6068-4. https://pubmed.ncbi.nlm.nih.gov/31492116/

5. Muhle, Hiltrud, von Spiczak, Sarah, Gaus, Verena, Stephani, Ulrich, Sander, Thomas. 2010. Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis. In Epilepsy research, 89, 319-26. doi:10.1016/j.eplepsyres.2010.02.004. https://pubmed.ncbi.nlm.nih.gov/20338729/