The Mas-related G protein-coupled receptors (MRGPRs) comprise a subfamily of GPCRs. MRGPRs family comprises almost 40 members which can be grouped into nine distinct subfamilies (MRGPRA to -H and -X) and almost all the members are still considered "orphan" with no endogenous ligands identified. However, several distinct peptides and amino acids are evaluated as potential ligands, including β-alanine, angiotensin-(1-7), alamandine, GABA, cortistatin-14, and cleavage products of proenkephalin, pro-opiomelanocortin, prodynorphin, or pro-neuropeptide-FF-A.
Most MRGPRs, including all MRGPRA, MRGPRB, and part of MRGPRC and MRGPRD subfamily members, are nearly and exclusively expressed in specific dorsal root and trigeminal ganglia neurons and play important roles in nociception, itch, or pruritus, and thermosensation. Some MRGPRs, such as human MRGPRX2 and rat MRGPRB3, are probably the long-sought low-affinity, low-selectivity receptors on mast cells that mediate IgE-independent degranulating actions. In vitro overexpression cells, MRGPRs present tumorigenic and proliferative actions when the accumulation exceeds a certain threshold, which is normally not reached in vivo. Some MRGPRs have been shown to be expressed in cardiovascular organs and exploited its protective actions in cardiovascular and metabolic diseases. The further investigations on MRGPRs reveal their physiologic and pathophysiologic functions with great therapeutic potency.
Here shows a part of members of MRGPRs, including MRGPRD to -G and MRGPRX1 to -X4. MRGPRD is the first identified non-orphan receptor that recognizes β-alanine as a ligand and its activation is transmitted by both Gq and Gi proteins onto changes of intracellular Ca2+ and cAMP. MRGPRE most likely binds MRGPRD to form heterodimers. MRGPRX1 can be activated by BAM22, a product of proenkephalin A metabolism. β-defensins (e.g., hBD2 and hBD3) and cathelicidines (e.g., LL-37), are ligands for MRGPRX2 receptor on human mast cells. For MRGPRF, MRGPRG, MRGPRX3 and MRGPRX4, no ligand has been described yet.
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