Rgs4, short for Regulator of G-protein signaling 4, is a negative regulator of G-protein signaling. It mainly functions through its GTPase-activating protein activity to constrain G protein-coupled receptor (GPCR)-mediated responses [2]. GPCRs are crucial for various physiological processes, and Rgs4's role in modulating G-protein signaling is of great biological importance. Genetic mouse models, such as KO mouse models, have been instrumental in studying Rgs4's functions.

In heart failure, Rgs4 is selectively upregulated among the RGS protein family in humans, suggesting its role in cardiac pathophysiology [1,7]. In glioblastoma, silencing Rgs4 inhibits glioma cancer stem cell growth, invasion, and migration, indicating its potential as a therapeutic target [3]. In rodent models of chronic pain, preventing Rgs4 action leads to recovery from mechanical and cold allodynia, showing its role in maintaining chronic pain states [4]. In asthma, Rgs4 affects airway hyper-responsiveness through GAP-independent mechanisms, with Rgs4 KO mice having decreased AHR due to increased production of the bronchodilator prostaglandin E2 by lung epithelial cells [2]. In cardiac fibrosis, inhibition of Rgs4 expression improves cardiac fibrosis, and overexpression of Rgs4 counteracts the anti-cardiac fibrosis effect of choline [5]. In the context of diet-induced obesity, siRNA-mediated knockdown of striatal Rgs4 in diet-induced obesity-susceptible rats decreased food intake, highlighting its role in feeding and obesity susceptibility [6]. In mouse prefrontal cortex, knockout of Rgs4 (RGS4KO) increases susceptibility to chronic variable stress and paradoxically enhances the antidepressant efficacy of ketamine [8].

In conclusion, Rgs4 plays essential roles in multiple biological processes and disease conditions. The use of gene knockout mouse models has significantly contributed to understanding its functions in areas such as heart failure, glioblastoma, chronic pain, asthma, cardiac fibrosis, obesity, and stress-related psychiatric disorders. This knowledge provides potential directions for therapeutic interventions targeting Rgs4 in these diseases.

References:

1. Del Calvo, Giselle, Baggio Lopez, Teresa, Lymperopoulos, Anastasios. . The therapeutic potential of targeting cardiac RGS4. In Therapeutic advances in cardiovascular disease, 17, 17539447231199350. doi:10.1177/17539447231199350. https://pubmed.ncbi.nlm.nih.gov/37724539/

2. Joshi, Ilin V, Chan, Eunice C, Lack, Justin B, Liu, Chengyu, Druey, Kirk M. 2024. RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms. In The Journal of biological chemistry, 300, 107127. doi:10.1016/j.jbc.2024.107127. https://pubmed.ncbi.nlm.nih.gov/38432633/

3. Guda, Maheedhara R, Velpula, Kiran K, Asuthkar, Swapna, Cain, Charlie P, Tsung, Andrew J. 2020. Targeting RGS4 Ablates Glioblastoma Proliferation. In International journal of molecular sciences, 21, . doi:10.3390/ijms21093300. https://pubmed.ncbi.nlm.nih.gov/32392739/

4. Avrampou, Kleopatra, Pryce, Kerri D, Ramakrishnan, Aarthi, Carr, Fiona B, Zachariou, Venetia. 2019. RGS4 Maintains Chronic Pain Symptoms in Rodent Models. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 39, 8291-8304. doi:10.1523/JNEUROSCI.3154-18.2019. https://pubmed.ncbi.nlm.nih.gov/31308097/

5. Guo, Jing, Hang, Pengzhou, Yu, Jie, Fan, Ziyi, Du, Zhimin. 2021. The association between RGS4 and choline in cardiac fibrosis. In Cell communication and signaling : CCS, 19, 46. doi:10.1186/s12964-020-00682-y. https://pubmed.ncbi.nlm.nih.gov/33892733/

6. Michaelides, Michael, Miller, Michael L, Egervari, Gabor, Volkow, Nora D, Hurd, Yasmin L. 2018. Striatal Rgs4 regulates feeding and susceptibility to diet-induced obesity. In Molecular psychiatry, 25, 2058-2069. doi:10.1038/s41380-018-0120-7. https://pubmed.ncbi.nlm.nih.gov/29955167/

7. Borges, Jordana I, Suster, Malka S, Lymperopoulos, Anastasios. 2023. Cardiac RGS Proteins in Human Heart Failure and Atrial Fibrillation: Focus on RGS4. In International journal of molecular sciences, 24, . doi:10.3390/ijms24076136. https://pubmed.ncbi.nlm.nih.gov/37047106/

8. Mitsi, Vasiliki, Ruiz, Anne, Polizu, Claire, Shen, Li, Zachariou, Venetia. 2024. RGS4 Actions in Mouse Prefrontal Cortex Modulate Behavioral and Transcriptomic Responses to Chronic Stress and Ketamine. In Molecular pharmacology, 105, 272-285. doi:10.1124/molpharm.123.000753. https://pubmed.ncbi.nlm.nih.gov/38351270/