Departmental Papers (Dental)
PMX-53 as a Dual CD88 antagonist and an Agonist for Mas-Related Gene 2 (MrgX2) in Human Mast Cells
Date of this Version
Human mast cells express the G protein coupled receptor (GPCR) for C5a (CD88). Previous studies indicated that C5a could cause mast cell degranulation, at least in part, via a mechanism similar to that proposed for basic neuropeptides such as substance P, possibly involving Mas-related gene 2 (MrgX2). We therefore sought to more clearly define the receptor specificity for C5a-induced mast cell degranulation. We found that LAD2, a human mast cell line, and CD34+ cell-derived primary mast cells express functional MrgX1 and MrgX2 but the immature human mast cell line HMC-1 does not. A potent CD88 antagonist, PMX-53 (10 nM) inhibited C5ainduced Ca2+ mobilization in HMC-1 cells, but at higher concentrations (≥30 nM) it caused degranulation in LAD2 mast cells, CD34+ cell-derived mast cells, and RBL-2H3 cells stably expressing MrgX2. PMX-53 did not, however, activate RBL-2H3 cells expressing MrgX1. Although C5a induced degranulation in LAD2 and CD34+ cell-derived mast cells, it did not activate RBL-2H3 cells expressing MrgX1 or MrgX2. Replacement of Trp with Ala and Arg with dArg abolished the ability of PMX-53 to inhibit C5a-induced Ca2+ mobilization in HMC-1 cells and to cause degranulation in RBL-2H3 cells expressing MrgX2. These findings demonstrate that C5a does not use MrgX1 or MrgX2 for mast cell degranulation. Moreover, it reveals the novel finding that PMX-53 functions as a potent CD88 antagonist and a low-affinity agonist for MrgX2. Furthermore, Trp and Arg residues are required for the ability of PMX53 to act as both a CD88 antagonist and a MrgX2 agonist. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.
Subramanian, H., Kashem, S. W., Collington, S. J., Qu, H., Lambris, J. D., & Ali, H. (2011). PMX-53 as a Dual CD88 antagonist and an Agonist for Mas-Related Gene 2 (MrgX2) in Human Mast Cells. Molecular Pharmacology, 79 (6), 1005-1013. http://dx.doi.org/10.1124/mol.111.071472
Date Posted: 10 February 2023
This document has been peer reviewed.