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  • Title: Bidirectional effects of protein kinase C activators. Studies with human neutrophils and platelet-activating factor.
    Author: O'Flaherty JT, Jacobson DP, Redman JF.
    Journal: J Biol Chem; 1989 Apr 25; 264(12):6836-43. PubMed ID: 2540163.
    Abstract:
    Protein kinase C (PKC) (Ca2+/phospholipid-dependent enzyme) activators stimulated human neutrophils to reduce the availability of high affinity receptors for platelet-activating factor. These effects were concentration dependent, irreversible, temperature sensitive, and antagonized by a PKC blocker. The activators also inhibited 1-O-alkyl-65% hexadecyl, 25% octadecyl-2-acetyl-sn-glycero-3-phosphocholine (PAF)-induced Ca2+ transients; this inhibition correlated precisely with receptor depletion. Contrastingly, PKC activators could enhance as well as inhibit PAF-induced degranulation. Inhibition of degranulation occurred only at concentrations of the activators which depressed high affinity PAF binding by greater than 75%. Cells treated with lesser activator concentrations responded to PAF with reduced but still substantial rises in cytosolic Ca2+, markedly increased degranulation, and markedly increased PKC mobilization. The last two responses, however, failed to occur in cells that were (a) calcium depleted, (b) treated with high activator concentrations (which inhibited virtually all PAF binding and PAF-induced Ca2+ transients), or (c) treated with PAF 5 min before a PKC activator (PAF-induced rises in cytosolic Ca2+ reversed in less than 5 min). Thus, activated PKC down-regulates high affinity PAF receptors. This tends to reduce neutrophil responses to PAF. On the other hand, PAF, perhaps by raising cytosolic Ca2+, acts synergistically with PKC activators in mobilizing PKC. This may tend to enhance function but seems capable of influencing only those responses that are elicited by PKC activators (e.g. degranulation but not Ca2+ transients). The complex and bidirectional effects of PKC activators on other receptor-mediated, calcium mobilizing agonists in various cell types may reflect these opposing mechanisms.
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