A mechanism for phorbol ester-mediated regulation of the PAF receptor in human neutrophils.
Phorbol esters induce rapid downregulation of PAF receptors on human neutrophils. The molecular mechanism responsible for this observation has not been elucidated. In the present study, treatment of neutrophils with PMA (10(-7) M) for 10 min caused a complete loss of PAF receptors from the cell surface as determined by specific radioligand binding. This loss of PAF receptors was associated with an inhibition of a PAF-induced increase in [Ca2+]i. Evidence presented in this study suggests that the rapid loss of PAF binding sites from the neutrophil surface is due to PMA-induced PAF receptor internalization and/or redistribution of cellular PAF receptors. This contention is based upon: (i) disruption of PMA-treated neutrophils exposed latent PAF binding sites, while PAF receptors downregulated following A23187 treatment failed to recover upon cell disruption; (ii) PMA-induced PAF receptor downregulation was not observed in cell homogenate preparations, suggesting that cellular integrity which facilitates receptor internalization or redistribution was required; (iii) cytochalasin B, an agent capable of disrupting microfilaments, attenuated PMA-induced PAF receptor downregulation. This phenomenon was reproduced in human mononuclear cells. Thus, the cellular basis for PMA-induced PAF receptor loss from human neutrophils and mononuclear leukocytes likely involves internalization or cellular redistribution of the PAF receptor.
Zhou
W
W
Department of Biochemistry, University of Texas Health Science Center, San Antonio 78284.
Olson
M S
MS
D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D015536:Down-Regulation; D004533:Egtazic Acid / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D000001:Calcimycin; D003571:Cytochalasin B; D004533:Egtazic Acid; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium