PMID- 9727041
OWN - NLM
STAT- MEDLINE
DCOM- 19981013
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 273
IP  - 37
DP  - 1998 Sep 11
TI  - High constitutive activity of the human formyl peptide receptor.
PG  - 24181-9
AB  - The formyl peptide receptor (FPR) couples to pertussis toxin (PTX)-sensitive 
      Gi-proteins to activate chemotaxis and exocytosis in neutrophils. PTX reduces not 
      only formyl peptide-stimulated but also agonist-independent ("basal") Gi-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 
      Gialpha2beta1gamma2 reconstituted N-formyl-L-methionyl-L-leucyl-L-phenylalanine 
      (FMLP)-stimulated guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) binding and 
      GTPgammaS-sensitive high affinity [3H]FMLP binding. The FPR "antagonist" 
      cyclosporin H (CsH) potently and efficiently reduced basal GTPgammaS binding in 
      Sf9 membranes. Another FPR antagonist, 
      N-t-butoxycarbonyl-L-phenylalanyl-L-leucyl-L-phenylalanyl-L-leucyl-L- 
      phenylalanine did not inhibit basal GTPgammaS binding but blocked the inhibitory 
      effect of CsH on GTPgammaS binding. Na+ reduced basal GTPgammaS 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.
FAU - Wenzel-Seifert, K
AU  - Wenzel-Seifert K
AD  - Howard Hughes Medical Institute, Stanford University Medical School, Stanford, 
      California 94305-5428, USA.
FAU - Hurt, C M
AU  - Hurt CM
FAU - Seifert, R
AU  - Seifert R
LA  - eng
GR  - GM 07365/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Receptors, Formyl Peptide)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Receptors, Peptide)
RN  - 0 (Recombinant Proteins)
RN  - 37589-80-3 (Guanosine 5'-O-(3-Thiotriphosphate))
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - 83HN0GTJ6D (Cyclosporine)
RN  - 9NEZ333N27 (Sodium)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go)
RN  - FUO6O3NDNH (cyclosporin H)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cell Membrane/physiology
MH  - Cyclosporine/pharmacology
MH  - GTP-Binding Protein alpha Subunits, Gi-Go/isolation & purification/metabolism
MH  - GTP-Binding Proteins/*metabolism
MH  - Guanosine 5'-O-(3-Thiotriphosphate)/metabolism/*pharmacology
MH  - Humans
MH  - Kinetics
MH  - Models, Chemical
MH  - N-Formylmethionine Leucyl-Phenylalanine/metabolism/*pharmacology
MH  - Receptors, Formyl Peptide
MH  - Receptors, Immunologic/agonists/antagonists & inhibitors/*metabolism
MH  - Receptors, Peptide/agonists/antagonists & inhibitors/*metabolism
MH  - Recombinant Proteins/metabolism
MH  - Sodium/pharmacology
MH  - Spodoptera
MH  - Transfection
EDAT- 1998/09/03 00:00
MHDA- 1998/09/03 00:01
CRDT- 1998/09/03 00:00
PHST- 1998/09/03 00:00 [pubmed]
PHST- 1998/09/03 00:01 [medline]
PHST- 1998/09/03 00:00 [entrez]
AID - S0021-9258(19)60259-0 [pii]
AID - 10.1074/jbc.273.37.24181 [doi]
PST - ppublish
SO  - J Biol Chem. 1998 Sep 11;273(37):24181-9. doi: 10.1074/jbc.273.37.24181.