Compound 48/80 activates mast cell phospholipase D via heterotrimeric GTP-binding proteins

¹Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1760, USA.

The Journal of Pharmacology and Experimental Therapeutics

|December 22, 1999

Summary

Researchers identified a novel signaling pathway involving pertussis toxin-sensitive G proteins that activates phospholipase D (PLD) in mast cells. This pathway, likely mediated by G protein beta-gamma subunits, offers new insights into cellular signaling mechanisms.

Area of Science:

Cellular Biology
Immunology
Signal Transduction

Background:

Phospholipase D (PLD) activation in RBL-2H3 mast cells is known to be stimulated by calcium, protein kinase C, and an unidentified signal.
Cholera toxin sensitivity suggests involvement of G(s) proteins, while pertussis toxin sensitivity points to G(i) proteins.

Purpose of the Study:

To identify the third signaling pathway involved in the synergistic activation of phospholipase D (PLD) in RBL-2H3 mast cells.
To elucidate the role of heterotrimeric GTP-binding proteins (G proteins) in PLD activation.

Main Methods:

Utilized quercetin to enhance G(alphai2) and G(alphai3) expression in RBL-2H3 cells.
Administered compound 48/80, a G(i) protein stimulant, and pertussis toxin or cholera toxin to assess PLD activation.
Investigated the role of calcium and protein kinase C in the response.
Examined the effect of recombinant G protein beta-gamma (G(betagamma)) subunits on PLD activation in permeabilized cells.

Main Results:

Enhanced expression of G(alphai2) and G(alphai3) led to compound 48/80-induced PLD activation, phospholipase C activation, and increased membrane GTPase activity.
PLD activation by compound 48/80 was blocked by pertussis toxin and enhanced by cholera toxin.
The response to compound 48/80 was only partially dependent on calcium and protein kinase C, indicating an independent component.
Recombinant G(betagamma) subunits synergized PLD activation by compound 48/80, while G(alpha) subunits did not.

Conclusions:

A third signaling pathway for PLD activation in RBL-2H3 mast cells involves pertussis toxin-sensitive G proteins, likely G(i2) or G(i3).
G protein beta-gamma subunits released from G(i) or G(s) proteins appear to provide a crucial signal for PLD activation.
This study identifies G protein betagamma subunits as key mediators in the synergistic activation of PLD.

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Compound 48/80 activates mast cell phospholipase D via heterotrimeric GTP-binding proteins

Area of Science:

Background:

Purpose of the Study:

Main Methods:

Main Results:

Conclusions:

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