MrgprD, a Mas-related G protein-coupled receptor, was first identified in small-diameter sensory neurons of mouse dorsal root ganglion (DRG). It has been implicated in multiple physiological functions such as somatosensation, especially in pain and itch response, and also in the modulation of murine intestinal motility [2,3,4]. It may be involved in pathways related to glutamate release, PKA-TRP-A1, and phospholipase C [1,4,5].

Ablation of MrgprD-expressing neurons led to increased expression of a mast cell gene module, resulting in increased mast cell degranulation and cutaneous inflammation, suggesting its role in maintaining skin homeostasis via glutamate-mediated suppression of mast cell hyperresponsiveness [1]. In neuropathic pain models, MrgprD was necessary for the initiation of mechanical hypersensitivity and cold allodynia but not heat allodynia, and facilitated by TRP-A1 through the PKA-TRP-A1 pathway [4]. Ablation of MrgprdCreERT2-marked neurons reduced nerve injury-induced mechanical allodynia and hyperalgesia [6].

In conclusion, MrgprD plays crucial roles in maintaining skin immune homeostasis, and in the development of neuropathic pain. Gene-knockout mouse models have been instrumental in revealing these functions, providing insights into potential therapeutic targets for skin inflammation and neuropathic pain management.

References:

1. Zhang, Shiqun, Edwards, Tara N, Chaudhri, Virendra K, Singh, Harinder, Kaplan, Daniel H. 2021. Nonpeptidergic neurons suppress mast cells via glutamate to maintain skin homeostasis. In Cell, 184, 2151-2166.e16. doi:10.1016/j.cell.2021.03.002. https://pubmed.ncbi.nlm.nih.gov/33765440/

2. Xu, Min, Zhang, Zhudi, Lan, Lei. 2022. Identification of MrgprD expression in mouse enteric neurons. In Cell and tissue research, 388, 479-484. doi:10.1007/s00441-022-03608-x. https://pubmed.ncbi.nlm.nih.gov/35258714/

3. Wang, Kaikai, Wang, Sashuang, Chen, Yan, Li, Changlin, Zhang, Xu. 2021. Single-cell transcriptomic analysis of somatosensory neurons uncovers temporal development of neuropathic pain. In Cell research, 31, 904-918. doi:10.1038/s41422-021-00479-9. https://pubmed.ncbi.nlm.nih.gov/33692491/

4. Wang, Changming, Gu, Leying, Ruan, Yonglan, Lan, Lei, Tang, Zongxiang. 2018. Facilitation of MrgprD by TRP-A1 promotes neuropathic pain. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 1360-1373. doi:10.1096/fj.201800615RR. https://pubmed.ncbi.nlm.nih.gov/30148678/

5. Yang, Yan, Sun, Yulin, Zhu, Chan, Sheng, Meixiao, Tang, Zongxiang. 2023. Allantoin induces pruritus by activating MrgprD in chronic kidney disease. In Journal of cellular physiology, 238, 813-828. doi:10.1002/jcp.30977. https://pubmed.ncbi.nlm.nih.gov/36879552/

6. Wang, Liangbiao, Su, Xiaojing, Yan, Jinjin, Liu, Xinfeng, Zhang, Yan. 2023. Involvement of Mrgprd-expressing nociceptors-recruited spinal mechanisms in nerve injury-induced mechanical allodynia. In iScience, 26, 106764. doi:10.1016/j.isci.2023.106764. https://pubmed.ncbi.nlm.nih.gov/37250305/