Receptor class desensitization of leukocyte chemoattractant receptors.
To better define their regulation, formylpeptide and C5a chemoattractant receptor cDNAs were transiently expressed with high efficiency (approximately 35-54%) in human kidney cells. As in neutrophils, both receptors were active in elevating intracellular calcium (ED50 approximately 0.5-1 nM). Agonist-specific desensitization for calcium elevation was observed for both chemoattractant receptors at doses of approximately 1 nM. Heterologous desensitization of formylpeptide, C5a, and alpha 1-adrenergic receptors required high doses of phorbol ester (100 nM phorbol 12-myristate 13-acetate). To further study the phenomenon of desensitization, formylpeptide and C5a receptor cDNAs were cotransfected resulting in approximately 80% of receptor-positive cells expressing both receptors. These cells also possessed endogenous alpha 1-adrenergic receptors. Interestingly, chemoattractant receptors were cross-desensitized by pretreatment with low doses of either C5a or formylmethionylleucylphenylalanine (10 nM) but not by the alpha 1-adrenergic agonist norepinephrine (up to 10 microM). Neither chemoattractant desensitized alpha 1-adrenergic receptors. This phenomenon was reproduced in human neutrophils. These data suggest a previously uncharacterized mechanism of receptor regulation, which is intermediate between homologous and heterologous desensitization. Class desensitization of chemoattractant receptors is less selective than homologous desensitization but is far more efficient and specific than heterologous desensitization. Receptor class desensitization may affect functional classes of receptors via modification of either the receptor or the shared guanine nucleotide-binding regulatory protein.
Didsbury
J R
JR
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Uhing
R J
RJ
Tomhave
E
E
Gerard
C
C
Gerard
N
N
Snyderman
R
R
D000260:Adenoviruses, Human / Q000235:genetics; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D015936:Complement C5a / Q000378:metabolism / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007668:Kidney; D007700:Kinetics; D007962:Leukocytes; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000378:metabolism / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection
D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a; D002217:Carbachol; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium; D009638:Norepinephrine