Gpr17, a G-protein-coupled receptor, is phylogenetically related to purinergic P2Y and CysLT receptors. It is mainly expressed in the CNS and in organs prone to ischemic damage [2]. Gpr17 is involved in various pathologies such as stroke, brain and spinal cord trauma, multiple sclerosis, and other diseases characterized by neuronal and myelin dysfunction. It also plays a role in oligodendrogenesis, myelination, and may be involved in energy homeostasis [2,3,4,5,8,9].

In KO/CKO mouse models and other loss-of-function experiments: Inhibition or knockdown of hippocampal Gpr17 attenuated lipopolysaccharide-induced cognitive impairment, inhibited Aβ production, regulated NF-κB/CREB/BDNF signaling, and suppressed neuroinflammation [1]. Intestinal Gpr17 deficiency improved glucose metabolism by promoting GLP-1 secretion [6]. Inhibition of Gpr17 in basolateral amygdala glutamatergic neurons improved anxiety-like behaviors in a chronic restraint stress mouse model [7]. Gpr17-null mice and mice with oligodendrocyte-specific knockout of Gpr17 had lean phenotypes on a high-fat diet, suggesting Gpr17 in oligodendrocytes regulates body weight [8].

In conclusion, Gpr17 is crucial in multiple biological processes. Model-based research, especially through Gpr17 KO/CKO mouse models, has revealed its significance in cognitive function, glucose metabolism, anxiety-like behaviors, and body weight regulation. These findings suggest Gpr17 could be a potential therapeutic target for diseases such as Alzheimer's disease, diabetes, obesity, and anxiety disorders [1,6,7,8].

References:

1. Liang, Yusheng, Kang, Xu, Zhang, Haiwang, Xu, Heng, Wu, Xian. 2023. Knockdown and inhibition of hippocampal GPR17 attenuates lipopolysaccharide-induced cognitive impairment in mice. In Journal of neuroinflammation, 20, 271. doi:10.1186/s12974-023-02958-9. https://pubmed.ncbi.nlm.nih.gov/37990234/

2. Marucci, Gabriella, Dal Ben, Diego, Lambertucci, Catia, Volpini, Rosaria, Buccioni, Michela. 2019. GPR17 receptor modulators and their therapeutic implications: review of recent patents. In Expert opinion on therapeutic patents, 29, 85-95. doi:10.1080/13543776.2019.1568990. https://pubmed.ncbi.nlm.nih.gov/30640576/

3. Wang, Jing, He, Xuelian, Meng, Huyan, Lu, Q Richard, He, Zhigang. 2020. Robust Myelination of Regenerated Axons Induced by Combined Manipulations of GPR17 and Microglia. In Neuron, 108, 876-886.e4. doi:10.1016/j.neuron.2020.09.016. https://pubmed.ncbi.nlm.nih.gov/33108748/

4. Lecca, Davide, Raffaele, Stefano, Abbracchio, Maria P, Fumagalli, Marta. 2020. Regulation and signaling of the GPR17 receptor in oligodendroglial cells. In Glia, 68, 1957-1967. doi:10.1002/glia.23807. https://pubmed.ncbi.nlm.nih.gov/32086854/

5. Dziedzic, Angela, Miller, Elzbieta, Saluk-Bijak, Joanna, Bijak, Michal. 2020. The GPR17 Receptor-A Promising Goal for Therapy and a Potential Marker of the Neurodegenerative Process in Multiple Sclerosis. In International journal of molecular sciences, 21, . doi:10.3390/ijms21051852. https://pubmed.ncbi.nlm.nih.gov/32182666/

6. Yan, Shijun, Conley, Jason M, Reilly, Austin M, Evans-Molina, Carmella, Ren, Hongxia. . Intestinal Gpr17 deficiency improves glucose metabolism by promoting GLP-1 secretion. In Cell reports, 38, 110179. doi:10.1016/j.celrep.2021.110179. https://pubmed.ncbi.nlm.nih.gov/34986353/

7. Nie, Ruizhe, Zhou, Xinting, Fu, Jiaru, Hong, Hao, Tang, Susu. 2024. GPR17 modulates anxiety-like behaviors via basolateral amygdala to ventral hippocampal CA1 glutamatergic projection. In Acta pharmaceutica Sinica. B, 14, 4789-4805. doi:10.1016/j.apsb.2024.08.005. https://pubmed.ncbi.nlm.nih.gov/39664418/

8. Ou, Zhimin, Ma, Yanchen, Sun, Yuxia, Zhao, Tong-Jin, Chen, Ying. . A GPR17-cAMP-Lactate Signaling Axis in Oligodendrocytes Regulates Whole-Body Metabolism. In Cell reports, 26, 2984-2997.e4. doi:10.1016/j.celrep.2019.02.060. https://pubmed.ncbi.nlm.nih.gov/30865888/

9. Fumagalli, Marta, Lecca, Davide, Coppolino, Giusy T, Parravicini, Chiara, Abbracchio, Maria P. . Pharmacological Properties and Biological Functions of the GPR17 Receptor, a Potential Target for Neuro-Regenerative Medicine. In Advances in experimental medicine and biology, 1051, 169-192. doi:10.1007/5584_2017_92. https://pubmed.ncbi.nlm.nih.gov/28828731/