Galr2, short for galanin receptor 2, is a G-protein coupled receptor (GPCR). It is implicated in the control and processing of painful stimuli, with expression in key nervous system tissues like dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. It is also involved in multiple biological processes such as adult hippocampal neurogenesis, reproduction-related regulation in GnRH neurons, and regulation of atrial fibrillation susceptibility. It may play a role in the epithelial-to-mesenchymal transition in salivary adenoid cystic carcinoma and in protecting the heart from ischemia/reperfusion injury [1,2,3,4,5,6].

In the context of disease, several studies have explored its potential as a drug target. For neuropathic pain, Galr2 is considered a possible drug target as its stimulation has a role in attenuating inflammatory and neuropathic pain, but key questions regarding its expression profile, receptor signalling, and ligand interactions need to be addressed before it can be a suitable target for investment [1]. In atrial fibrillation, knockout of Galr2 in cardiomyocytes (GALR2-cKO mice) led to a higher incidence of AF, associated with increased inward rectifying K⁺ current (IK1) and intracellular Ca²⁺ overload, suggesting that Spexin may reduce atrial fibrillation susceptibility by acting on GalR2 [6].

In conclusion, Galr2 has diverse biological functions in pain regulation, neurogenesis, cancer progression, heart protection, and atrial fibrillation regulation. Mouse models, such as the GALR2-cKO mice, have been instrumental in revealing its role in atrial fibrillation, highlighting its potential as a therapeutic target in related disease areas.

References:

1. Rich, Kirsty, Rehman, Samrina, Jerman, Jeff, Wilkinson, Graeme. 2022. Investigating the potential of GalR2 as a drug target for neuropathic pain. In Neuropeptides, 98, 102311. doi:10.1016/j.npep.2022.102311. https://pubmed.ncbi.nlm.nih.gov/36580831/

2. Alvarez-Contino, Jose Erik, Díaz-Sánchez, Estela, Mirchandani-Duque, Marina, Borroto-Escuela, Dasiel O, Narváez, Manuel. 2023. GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant-like effects involving BDNF actions. In Journal of cellular physiology, 238, 459-474. doi:10.1002/jcp.30944. https://pubmed.ncbi.nlm.nih.gov/36599082/

3. Wang, Jun, Yang, Zihui, Liu, Yuanyang, Yang, Xinjie, Wei, Jianhua. 2022. The GAL/GALR2 axis promotes the perineural invasion of salivary adenoid cystic carcinoma via epithelial-to-mesenchymal transition. In Cancer medicine, 12, 4496-4509. doi:10.1002/cam4.5181. https://pubmed.ncbi.nlm.nih.gov/36039037/

4. Serebryakova, Larisa, Veselova, Oksana, Studneva, Irina, Sidorova, Maria, Pisarenko, Oleg. 2023. Exogenous GalR2-specific peptide agonist as a tool for treating myocardial ischemia/reperfusion injury. In Fundamental & clinical pharmacology, 37, 1109-1118. doi:10.1111/fcp.12925. https://pubmed.ncbi.nlm.nih.gov/37249014/

5. Wang, Lu, Tran, Andy, Lee, Juliette, Belsham, Denise D. 2020. Palmitate differentially regulates Spexin, and its receptors Galr2 and Galr3, in GnRH neurons through mechanisms involving PKC, MAPKs, and TLR4. In Molecular and cellular endocrinology, 518, 110991. doi:10.1016/j.mce.2020.110991. https://pubmed.ncbi.nlm.nih.gov/32841709/

6. Li, Desheng, Liu, Yang, Li, Changzhu, Li, Yue, Pan, Zhenwei. 2024. Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2. In Circulation, 150, 111-127. doi:10.1161/CIRCULATIONAHA.123.067517. https://pubmed.ncbi.nlm.nih.gov/38726666/