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J Biol Chem, Vol. 273, Issue 37, 24181-24189, September 11, 1998

High Constitutive Activity of the Human Formyl Peptide Receptor

From the Howard Hughes Medical Institute, Stanford University Medical School, Stanford, California 94305-5428

The formyl peptide receptor (FPR) couples to pertussis toxin (PTX)-sensitive G_i-proteins to activate chemotaxis and exocytosis in neutrophils. PTX reduces not only formyl peptide-stimulated but also agonist-independent ("basal") G_i-protein activity, suggesting that the FPR is constitutively active. We aimed at identifying an inverse FPR agonist, i.e. a compound that suppresses constitutive FPR activity. In Sf9 insect cell membranes, the G-protein heterotrimer G_i212 reconstituted N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-stimulated guanosine 5'-O-(3-thiotriphosphate) (GTPS) binding and GTPS-sensitive high affinity [³H]FMLP binding. The FPR "antagonist" cyclosporin H (CsH) potently and efficiently reduced basal GTPS binding in Sf9 membranes. Another FPR antagonist, N-t-butoxycarbonyl-L-phenylalanyl-L-leucyl-L-phenylalanyl-L-leucyl-L-phenylalanine did not inhibit basal GTPS binding but blocked the inhibitory effect of CsH on GTPS binding. Na⁺ reduced basal GTPS binding and eliminated the inhibitory effect of CsH. Similar effects of FMLP, CsH, and Na⁺ as in Sf9 membranes were observed with FPR expressed in the mammalian cell line HEK293. Our data show that the human FPR possesses high constitutive activity. CsH is an inverse FPR agonist and stabilizes the FPR in an inactive state. Na⁺ also stabilizes the FPR in an inactive state and, thereby, diminishes inverse agonist efficacy.

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