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Vol. 292, Issue 1, 122-130, January 2000

Compound 48/80 Activates Mast Cell Phospholipase D via Heterotrimeric GTP-Binding Proteins

Ahmed Chahdi, Paul F. Fraundorfer and Michael A. Beaven

Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Previous studies have indicated the presence of a cholera toxin-sensitive phospholipase D (PLD) in cultured RBL-2H3 mast cells that is synergistically activated via calcium, protein kinase C, and another unidentified signal. Here we identify a third potential signal for activation transduced by a pertussis toxin-sensitive trimeric GTP-binding protein, most likely via Gi2 or Gi3. Quercetin-treated RBL-2H3 cells in which expression of Galpha i2 and Galpha i3 is enhanced more than 7-fold respond to the Gi stimulant compound 48/80 with the activation of PLD, a transient activation of phospholipase C, and enhanced membrane GTPase activity. The activation of PLD was blocked in pertussis toxin-treated cells and, as with other stimulants of PLD, was enhanced in cholera toxin-treated cells. The PLD response to compound 48/80 was only partially inhibited by calcium deprivation and inhibition of protein kinase C to indicate a component of the response that was independent of calcium, protein kinase C, and, presumably, phospholipase C. Based on these and other data, we hypothesized that beta gamma -subunits, released from Gi2 or Gi3 by compound 48/80 or from Gs by cholera toxin, provide an additional signal for the activation of PLD. Consistent with this hypothesis, recombinant Gbeta 2gamma 2 subunits, but not Galpha i-3 subunits, at concentrations of 50 to 300 nM markedly synergized PLD activation by compound 48/80 in permeabilized RBL-2H3 cells.

0022-3565/0/2921-0122$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by U.S. Government


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