Receptor Class Desensitization of Leukocyte Chemoattractant Receptors

To better define their regulation, formylpeptide and C5a chemoattractant receptor cDNAs were transiently expressed with high efficiency (≈ 35-54%) in human kidney cells. As in neutrophils, both receptors were active in elevating intracellular calcium (ED50≈ 0.5-1 nM). Agonist-specific desensitization for calcium elevation was observed for both chemoattractant receptors at doses of ≈ 1 nM. Heterologous desensitization of formylpeptide, C5a, and α1-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 ≈ 80% of receptor-positive cells expressing both receptors. These cells also possessed endogenous α1-adrenergic receptors. Interestingly, chemoattractant receptors were cross-desensitized by pretreatment with low doses of either C5a or formylmethionylleucylphenylalanine (10 nM) but not by the α1-adrenergic agonist norepinephrine (up to 10 μ M). Neither chemoattractant desensitized α1-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.