PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells

Mol Pharmacol. 2011 Jun;79(6):1005-13. doi: 10.1124/mol.111.071472. Epub 2011 Mar 11.


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 C5a-induced Ca(2+) 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 Ca(2+) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Complement C5a / antagonists & inhibitors
  • Humans
  • Mast Cells / drug effects*
  • Nerve Tissue Proteins / agonists*
  • Peptides, Cyclic / pharmacology*
  • Receptor, Anaphylatoxin C5a
  • Receptors, Complement / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Neuropeptide / agonists*
  • Reverse Transcriptase Polymerase Chain Reaction


  • AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg)
  • C5AR1 protein, human
  • MRGPRX2 protein, human
  • Nerve Tissue Proteins
  • Peptides, Cyclic
  • Receptor, Anaphylatoxin C5a
  • Receptors, Complement
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Complement C5a