# OXGR1

## Overview
OXGR1, or oxoglutarate receptor 1, is a gene that encodes a G protein-coupled receptor (GPCR) involved in various physiological processes across different tissues. The protein product of OXGR1, also known as oxoglutarate receptor 1, is integral to cellular signaling pathways that regulate functions such as mucociliary clearance in the respiratory system, blood flow and muscle metabolism in skeletal muscle, and energy expenditure in the adrenal gland. It is activated by ligands such as itaconate and α-ketoglutarate, which trigger intracellular signaling cascades essential for maintaining homeostasis and responding to metabolic demands (Zeng2023The; Yang2022AKGOXGR1). OXGR1's role extends to clinical significance, where its expression and function are linked to conditions like otitis media, hepatocellular carcinoma, and male fertility issues, highlighting its importance in both health and disease (Lin2017Panel; Lu2009Aberrant; Xu2022Smooth).

## Function
OXGR1, or oxoglutarate receptor 1, is a G protein-coupled receptor (GPCR) that plays a significant role in various physiological processes. In the respiratory system, OXGR1 is expressed in the respiratory epithelium and is crucial for mucociliary clearance (MCC), a process essential for removing pathogens and debris from the airways. Itaconate (ITA), an immunometabolite, acts as an orthosteric agonist for OXGR1, activating intracellular signaling pathways that lead to calcium mobilization and ERK phosphorylation, which are vital for MCC and the pulmonary innate immune response (Zeng2023The).

In skeletal muscle, OXGR1 is expressed in vascular smooth muscle cells (VSMCs) and is involved in regulating blood flow and muscle metabolism. It interacts with α-ketoglutarate (AKG), promoting muscle hypertrophy and enhancing endurance by facilitating blood flow and muscle fiber conversion. This signaling is crucial for maintaining capillary density and muscle function (Yang2022AKGOXGR1).

OXGR1 is also expressed in the adrenal gland, where it mediates the effects of AKG on energy expenditure and fat metabolism. It stimulates the release of epinephrine, enhancing thermogenesis and lipolysis, which are important for exercise-induced metabolic benefits and combating obesity (Yuan2020Exercise‐induced).

## Clinical Significance
Mutations and alterations in the expression of the OXGR1 gene have been implicated in several diseases and conditions. In otitis media (OM), a condition affecting the middle ear, deficiency in OXGR1 is associated with the presence of inflammatory cells, changes in the mucosal epithelium, and fluid accumulation in the middle ear, suggesting its role in the development of OM (Lin2017Panel). In oxgr1 knockout mice, spontaneous otitis media with effusion (OME) develops, characterized by hearing impairment and chronic tissue injury, indicating a non-infectious cause of OME linked to OXGR1 deficiency (Kerschner2013A).

In hepatocellular carcinoma (HCC), OXGR1 is frequently hypermethylated, which correlates with reduced mRNA levels. This hypermethylation is associated with cirrhosis and HCV infection, and its restoration can increase sensitivity to certain anticancer drugs, suggesting a potential role in cancer progression and treatment response (Lu2009Aberrant).

OXGR1 also plays a role in male fertility, where its deficiency impairs epididymal sperm maturation and function, leading to abnormalities in sperm morphology and reduced fertility. This suggests that OXGR1 is crucial for maintaining normal sperm health and function (Xu2022Smooth).

## Interactions
OXGR1, or oxoglutarate receptor 1, is known to participate in several protein interactions that influence its signaling pathways. One significant interaction is with the COP9 Constitutive Photomorphogenic Homolog Subunit 5 (COPS5), also known as CSN5 or JAB1. This interaction was identified using a yeast two-hybrid screen with the cytoplasmic carboxy-terminus region of OXGR1 as bait. The interaction between OXGR1 and CSN5 was confirmed through immunoprecipitation analysis in cardiomyocytes. CSN5 is involved in various cellular processes, including kinase signaling and protein degradation, and its expression is modulated by pressure overload in cardiac tissue (Omede2016The).

OXGR1 also forms a molecular complex with the CSN5-TYK2 complex, which is implicated in the regulation of the STAT3 signaling pathway. This interaction is particularly relevant in the context of cardiac hypertrophy, where OXGR1 acts as a suppressor by modulating STAT3 signaling through its interactions with CSN5 and TYK2 (Omede2016The).

These interactions highlight the role of OXGR1 in various signaling pathways, particularly those related to cardiac function and hypertrophy, by modulating the activity of key proteins involved in these processes.


## References


[1. (Zeng2023The) Yi-Rong Zeng, Jun-Bin Song, Dezheng Wang, Zi-Xuan Huang, Cheng Zhang, Yi-Ping Sun, Gang Shu, Yue Xiong, Kun-Liang Guan, Dan Ye, and Pu Wang. The immunometabolite itaconate stimulates oxgr1 to promote mucociliary clearance during the pulmonary innate immune response. Journal of Clinical Investigation, March 2023. URL: http://dx.doi.org/10.1172/jci160463, doi:10.1172/jci160463. This article has 23 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1172/jci160463)

[2. (Kerschner2013A) Joseph E. Kerschner, Wenzhou Hong, Steven R. Taylor, John A. Kerschner, Pawjai Khampang, Kay C. Wrege, and Paula E. North. A novel model of spontaneous otitis media with effusion (ome) in the oxgr1 knock-out mouse. International Journal of Pediatric Otorhinolaryngology, 77(1):79–84, January 2013. URL: http://dx.doi.org/10.1016/j.ijporl.2012.09.037, doi:10.1016/j.ijporl.2012.09.037. This article has 27 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ijporl.2012.09.037)

[3. (Yuan2020Exercise‐induced) Yexian Yuan, Pingwen Xu, Qingyan Jiang, Xingcai Cai, Tao Wang, Wentong Peng, Jiajie Sun, Canjun Zhu, Cha Zhang, Dong Yue, Zhihui He, Jinping Yang, Yuxian Zeng, Man Du, Fenglin Zhang, Lucas Ibrahimi, Sarah Schaul, Yuwei Jiang, Jiqiu Wang, Jia Sun, Qiaoping Wang, Liming Liu, Songbo Wang, Lina Wang, Xiaotong Zhu, Ping Gao, Qianyun Xi, Cong Yin, Fan Li, Guli Xu, Yongliang Zhang, and Gang Shu. Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through oxgr1‐dependent adrenal activation. The EMBO Journal, February 2020. URL: http://dx.doi.org/10.15252/embj.2019103304, doi:10.15252/embj.2019103304. This article has 40 citations.](https://doi.org/10.15252/embj.2019103304)

[4. (Lu2009Aberrant) Chang‐Yi Lu, Sen‐Yung Hsieh, Yen‐Jung Lu, Chi‐Sheng Wu, Lih‐Chyang Chen, Shao‐Jung Lo, Cheng‐Tao Wu, Min‐Yuan Chou, Tim Hui‐Ming Huang, and Yu‐Sun Chang. Aberrant dna methylation profile and frequent methylation of klk10 and oxgr1 genes in hepatocellular carcinoma. Genes, Chromosomes and Cancer, 48(12):1057–1068, September 2009. URL: http://dx.doi.org/10.1002/gcc.20708, doi:10.1002/gcc.20708. This article has 28 citations.](https://doi.org/10.1002/gcc.20708)

[5. (Xu2022Smooth) Chang Xu, Yexian Yuan, Cha Zhang, Yuchuan Zhou, Jinping Yang, Huadong Yi, Ishwari Gyawali, Jingyi Lu, Sile Guo, Yunru Ji, Chengquan Tan, Songbo Wang, Yongliang Zhang, Qingyan Jiang, and Gang Shu. Smooth muscle akg/oxgr1 signaling regulates epididymal fluid acid–base balance and sperm maturation. Life Metabolism, 1(1):67–80, July 2022. URL: http://dx.doi.org/10.1093/lifemeta/loac012, doi:10.1093/lifemeta/loac012. This article has 3 citations.](https://doi.org/10.1093/lifemeta/loac012)

[6. (Omede2016The) Ameh Omede, Min Zi, Sukhpal Prehar, Arfa Maqsood, Nicholas Stafford, Mamas Mamas, Elizabeth Cartwright, and Delvac Oceandy. The oxoglutarate receptor 1 (oxgr1) modulates pressure overload-induced cardiac hypertrophy in mice. Biochemical and Biophysical Research Communications, 479(4):708–714, October 2016. URL: http://dx.doi.org/10.1016/j.bbrc.2016.09.147, doi:10.1016/j.bbrc.2016.09.147. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.bbrc.2016.09.147)

[7. (Lin2017Panel) Jizhen Lin, Hena Hafrén, Joseph Kerschner, Jian‐Dong Li, Steve Brown, Qing Y. Zheng, Diego Preciado, Yoshihisa Nakamura, Qiuhong Huang, and Yan Zhang. Panel 3: genetics and precision medicine of otitis media. Otolaryngology–Head and Neck Surgery, April 2017. URL: http://dx.doi.org/10.1177/0194599816685559, doi:10.1177/0194599816685559. This article has 5 citations.](https://doi.org/10.1177/0194599816685559)

[8. (Yang2022AKGOXGR1) Jinping Yang, Guli Xu, Yiming Xu, Pei Luo, Yexian Yuan, Lin Yao, Jingjing Zhou, Yunlong Zhu, Ishwari Gyawali, Chang Xu, Jinlong Feng, Zewei Ma, Yuxian Zeng, Songbo Wang, Ping Gao, Canjun Zhu, Qingyan Jiang, and Gang Shu. Akg/oxgr1 promotes skeletal muscle blood flow and metabolism by relaxing vascular smooth muscle. Life Metabolism, 1(3):285–297, September 2022. URL: http://dx.doi.org/10.1093/lifemeta/loac026, doi:10.1093/lifemeta/loac026. This article has 1 citations.](https://doi.org/10.1093/lifemeta/loac026)