Gpr151, an orphan G protein-coupled receptor, has been implicated in various biological functions. It is highly conserved across mammals and has orthologs in species like zebrafish and chickens. Gpr151 is expressed in the habenula complex, spinal cord neurons, and dorsal root ganglia, and is thought to be involved in pain modulation, reward-seeking behavior, and may play a role in glucose metabolism and regulation of body mass index [4].

In nociceptive sensory neurons, conditional knockout of Gpr151 in adult mice significantly alleviated chronic constriction injury-induced neuropathic pain-like behavior without affecting basal nociception. It was required for chronic constriction injury-induced neuronal hyperexcitability and upregulation of CSF1, and coupled with P2X3 ion channels to promote their functional activities in neuropathic pain-like hypersensitivity [1]. In trigeminal nerve injury, global mutation or knockdown of Gpr151 in the trigeminal ganglion attenuated mechanical allodynia, and Gpr151 was found to activate ERK through Gβγ and induce neuroinflammation-related gene expression [3]. In terms of body mass index, while some studies associated its variants with reduced BMI and T2D risk, complete human knockouts and Gpr151 -/- mice on normal chow showed no difference in body weight, and higher body weight on a high-fat diet, indicating that Gpr151 antagonism may not be a compelling obesity treatment [2]. Also, Gpr151 -/- mice showed reduced social preference compared to Gpr151+/+ mice, suggesting its role in social reward [5].

In conclusion, Gpr151 plays a key role in pain-related processes, especially neuropathic pain, as demonstrated by gene knockout models. Its role in metabolic and social behaviors is also emerging, although its potential as a therapeutic target for obesity remains uncertain. These gene-knockout-based studies have enhanced our understanding of Gpr151's functions in these biological processes and disease-related conditions.

References:

1. Xia, Li-Ping, Luo, Hao, Ma, Qiang, Hu, Hailan, Xu, Zhen-Zhong. . GPR151 in nociceptors modulates neuropathic pain via regulating P2X3 function and microglial activation. In Brain : a journal of neurology, 144, 3405-3420. doi:10.1093/brain/awab245. https://pubmed.ncbi.nlm.nih.gov/34244727/

2. Gurtan, Allan, Dominy, John, Khalid, Shareef, Frossard, Philippe, Saleheen, Danish. 2022. Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index. In PLoS genetics, 18, e1010093. doi:10.1371/journal.pgen.1010093. https://pubmed.ncbi.nlm.nih.gov/35381001/

3. Jiang, Bao-Chun, Zhang, Jing, Wu, Bin, Wu, Hao, Gao, Yong-Jing. . G protein-coupled receptor GPR151 is involved in trigeminal neuropathic pain through the induction of Gβγ/extracellular signal-regulated kinase-mediated neuroinflammation in the trigeminal ganglion. In Pain, 162, 1434-1448. doi:10.1097/j.pain.0000000000002156. https://pubmed.ncbi.nlm.nih.gov/33239523/

4. DePasquale, Olivia, O'Brien, Chris, Gordon, Baila, Barker, David J. 2025. The Orphan Receptor GPR151: Discovery, Expression, and Emerging Biological Significance. In ACS chemical neuroscience, 16, 1639-1646. doi:10.1021/acschemneuro.4c00780. https://pubmed.ncbi.nlm.nih.gov/40295925/

5. Allain, Florence, Carter, Michelle, Dumas, Sylvie, Darcq, Emmanuel, Kieffer, Brigitte L. 2022. The mu opioid receptor and the orphan receptor GPR151 contribute to social reward in the habenula. In Scientific reports, 12, 20234. doi:10.1038/s41598-022-24395-z. https://pubmed.ncbi.nlm.nih.gov/36424418/