MrgprD, a Mas-related G protein-coupled receptor, was first identified in small-diameter sensory neurons of mouse dorsal root ganglion (DRG). It is involved in somatosensation, especially in pain and itch response, and also participates in the modulation of murine intestinal motility [2]. It has been associated with pathways related to pain, itch, and neuroimmune regulation. Genetic models, such as MrgprD-KO mouse models, are valuable for studying its functions.

Ablation of MrgprD-expressing neurons increased expression of a mast cell gene module, leading to increased mast cell degranulation and cutaneous inflammation, indicating that MrgprD-expressing neurons suppress mast cell hyperresponsiveness and skin inflammation via glutamate release [1]. In nerve injury-induced mechanical allodynia, ablation of MrgprdCreERT2-marked neurons reduced mechanical allodynia and hyperalgesia, uncovering the involvement of Mrgprd+ nociceptors in nerve injury-induced mechanical pain [4]. MrgprD is also essential in cold allodynia in chronic constriction injury (CCI)-induced neuropathic pain through the PKA-TRP-A1 pathway [3].

In conclusion, MrgprD plays crucial roles in multiple biological processes, especially in the regulation of pain, itch, and skin and gut homeostasis. The study of MrgprD KO mouse models has provided insights into its role in neuropathic pain, cutaneous inflammation, and potentially in the pathophysiology of the gastrointestinal tract, offering potential therapeutic targets for these disease areas.