Rgs6, a member of the R7 subfamily of Regulator of G protein signaling (RGS) proteins, acts as a gatekeeper for cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. It specifically modulates Gαi/o protein activity via its RGS domain, which is crucial for neuronal responses to neurotransmitters in the central nervous system (CNS). Additionally, it has G protein-independent functions in promoting apoptotic and growth-suppressive pathways [1,3].

In mouse models, Rgs6 deletion has shown distinct behavioral phenotypes. For example, it leads to ataxia, reduced anxiety and depression, enhanced analgesia, and increased parasympathetic tone due to potentiated signaling by related GPCRs [3]. In the context of diseases, Rgs6 knockdown in SCI mouse models suppressed oxidative stress, inflammation, and the progression of SCI, as Rgs6 elevation during SCI deactivated the AMP-activated protein kinase (AMPK) pathway [2]. In an Alzheimer's mouse model, Rgs6 deletion in dentate gyrus neuronal progenitors abolished the exercise-induced recovery of hippocampal neurogenesis, learning, and memory [4]. Also, RGS6-/-mice exhibit diminished binge-like alcohol consumption [5].

In conclusion, Rgs6 plays essential roles in both G protein-dependent CNS function and G protein-independent cancer-related processes. Gene knockout mouse models have been instrumental in revealing its role in various disease conditions such as CNS pathologies (including alcoholism, anxiety/depression, Parkinson's disease, SCI, and Alzheimer's disease) and potentially in cancer. Understanding Rgs6 function provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Ahlers, Katelin E, Chakravarti, Bandana, Fisher, Rory A. 2016. RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer. In The AAPS journal, 18, 560-72. doi:10.1208/s12248-016-9899-9. https://pubmed.ncbi.nlm.nih.gov/27002730/

2. Dao, Wenxin, Xiao, Zhe, Yang, Weize, Xia, Hongxia, Lu, Zuneng. 2022. RGS6 Drives Spinal Cord Injury by Inhibiting AMPK Pathway in Mice. In Disease markers, 2022, 4535652. doi:10.1155/2022/4535652. https://pubmed.ncbi.nlm.nih.gov/35510037/

3. Stewart, Adele, Maity, Biswanath, Fisher, Rory A. 2015. Two for the Price of One: G Protein-Dependent and -Independent Functions of RGS6 In Vivo. In Progress in molecular biology and translational science, 133, 123-51. doi:10.1016/bs.pmbts.2015.03.001. https://pubmed.ncbi.nlm.nih.gov/26123305/

4. Spicer, Mackenzie M, Yang, Jianqi, Fu, Daniel, Atasoy, Deniz, Fisher, Rory A. 2023. RGS6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in an Alzheimer's mouse model. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.04.17.537272. https://pubmed.ncbi.nlm.nih.gov/39185171/

5. DeBaker, Margot C, Mitten, Eric H, Rose, Timothy R, Lee, Anna M, Wickman, Kevin. 2023. RGS6 negatively regulates inhibitory G protein signaling in dopamine neurons and positively regulates binge-like alcohol consumption in mice. In British journal of pharmacology, 180, 2140-2155. doi:10.1111/bph.16071. https://pubmed.ncbi.nlm.nih.gov/36929333/