Role of guanine nucleotide binding protein in the activation of polyphosphoinositide phosphodiesterase.
Interaction of ligands with 'Ca2+-mobilizing' receptors is thought to result in the generation of two second messengers, inositol trisphosphate and diacylglycerol, from a common substrate, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) (refs 1, 2), a component of plasma membranes. It is not known how the occupation of such receptors is translated into the activation of the catalytic unit polyphosphoinositide (PPI) phosphodiesterase, and then to cellular activation, but our recent experiments suggest that GTP regulatory proteins may be involved. In mast cells, non-hydrolysable analogues of GTP introduced and then trapped in the cytosol are able to substitute for external ligands in inducing exocytosis, a well-defined Ca2+-dependent process, suggesting that guanine nucleotide regulatory proteins may act by stimulating the catalytic activity of the PPI phosphodiesterase. We now provide evidence that mast cell secretion is inhibited by internalized neomycin, a compound known to interact with PPI. We also show that the PPI phosphodiesterase of human neutrophil plasma membranes can be activated simply by adding GTP analogues in the presence of concentrations of Ca2+ that pertain in unstimulated cells. These findings strongly support the idea that the coupling factor linking receptor and PPI phosphodiesterase is a guanine nucleotide binding protein analogous to those involved in the activation and inhibition of adenylate cyclase.
Cockcroft
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Gomperts
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D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D008407:Mast Cells / Q000201:enzymology; D009504:Neutrophils / Q000201:enzymology; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011817:Rabbits; D013873:Thionucleotides / Q000494:pharmacology
D013873:Thionucleotides; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D019204:GTP-Binding Proteins; D002118:Calcium