Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P19086 (Galphaz)
 110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of guanine nucleotide-binding proteins (G proteins) in the cAMP-dependent action of serotonin (5-HT) and the antagonistic action of the neuropeptide Phe-Met-Arg-Phe-NH2 (FMRF-amide), mediated by the lipoxygenase metabolites of arachidonic acid, was investigated in Aplysia sensory neurons. Intracellular injection of guanosine 5'-[gamma-thio]triphosphate (GTP[gamma-S]) mimics the hyperpolarizing action of FMRF-amide due to activation of the S K+ current and alters the transient response to FMRF-amide into an irreversible (or only partially reversible) response. At higher concentrations, GTP[gamma-S] occludes the response to FMRF-amide. Injection of activated pertussis toxin inhibits the response to FMRF-amide but not to 5-HT. Injection of guanosine 5'-[beta-thio]diphosphate inhibits the response to FMRF-amide by approximately equal to 50% and completely blocks the response to 5-HT. Three lines of evidence suggest that the FMRF-amide-activated G protein is involved at an early stage of the arachidonic acid cascade, prior to the release of arachidonate. (i) Pertussis toxin injection blocks the hyperpolarizing response to FMRF-amide but not to exogenously applied arachidonic acid. (ii) Two blockers of the arachidonic acid cascade inhibit the hyperpolarizing responses to both FMRF-amide and GTP[gamma-S] (and unmask a 5-HT-like depolarizing response to the nucleotide). (iii) Concentrations of GTP[gamma-S] that alter the kinetics of the FMRF-amide response have no effect on the hyperpolarizing response to arachidonic acid. We conclude that a pertussis toxin-sensitive G protein most likely acts to couple the FMRF-amide receptor to phospholipase activation and arachidonic acid release, whereas a pertussis toxin-insensitive G protein couples the 5-HT receptor to adenylate cyclase.
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PMID:Role of two different guanine nucleotide-binding proteins in the antagonistic modulation of the S-type K+ channel by cAMP and arachidonic acid metabolites in Aplysia sensory neurons. 284 23

In neutrophils, activation of receptors for the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP) leads to changes in intracellular events such as phosphoinositide turnover and Ca2+ mobilization. Studies have shown that activation of the cloned fMLP receptor can also lead to inhibition of cyclic AMP (cAMP) accumulation [Lang, Boulay, Li and Wollheim (1993) EMBO J. 12, 2671-2679; Uhing, Gettys, Tomhave, Snyderman and Didsbury (1992) Biochem. Biophys. Res. Commun. 183, 1033-1039]. These responses are apparently mediated through pertussis toxin-sensitive Gi proteins. Since other chemotactic factor receptors can couple to multiple G proteins, we examined the ability of the fMLP receptor to utilize a pertussis toxin-insensitive G protein, Gz, in its signal transduction pathways. The human fMLP receptor was transiently expressed in 293 and Ltk- cells, and subsequently assayed for receptor-mediated inhibition of cAMP accumulation and stimulation of phosphoinositide-specific phospholipase C. In transfected 293 cells, fMLP inhibited choriogonadotropin-stimulated cAMP accumulation by 50% and the response could be abolished by pertussis toxin. Co-expression of the fMLP receptor with the alpha subunit of Gz rendered the fMLP response pertussis toxin-insensitive, indicating that the endogenous Gi proteins can be substituted efficiently by Gz. In contrast, Ltk- cells expressing the fMLP receptor were able to respond to fMLP with an increase in the production of inositol phosphates, but this response was completely abolished by pertussis toxin even in cells co-expressing the alpha subunit of Gz. Thus, although both signalling pathways appeared to utilize Gi-like proteins, Gz can only replace Gi in mediating inhibition of cAMP accumulation, and not in the stimulation of phospholipase C. Differential interaction with Gz might represent a novel mechanism by which fMLP receptors regulate intracellular events.
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PMID:Differential coupling of the formyl peptide receptor to adenylate cyclase and phospholipase C by the pertussis toxin-insensitive Gz protein. 761 76

The capacity of N-formylmethionyl-leucyl-phenylalanine (fMLP) and C5a receptors to regulate type II adenylyl cyclase was examined in transient transfection studies. Coexpression of either one of the chemoattractant receptors with type II adenylyl cyclase in human embryonic kidney 293 cells allowed the corresponding chemotactic factor to stimulate cAMP accumulation in a dose-dependent manner. The chemoattractant-induced stimulation of type II adenylyl cyclase was absolutely dependent on the presence of GTP-bound alpha subunit of GS, as revealed by the coexpression of alpha s-Q227L, a constitutively activated mutant of alpha s. Stimulation of type II adenylyl cyclase by either fMLP or C5a was mediated via pertussis toxin-sensitive Gi-like proteins, because the response was abrogated by the toxin. The ability of Gz (a pertussis toxin-insensitive G protein that can couple to a number of Gi-linked receptors) to replace Gi in chemoattractant-induced stimulation of type II adenylyl cyclase was examined. The chemoattractant-induced response became insensitive to pertussis toxin upon coexpression of the alpha subunit of Gz. Interestingly, coexpression of alpha z significantly enhanced the chemotactic factor-stimulated type II adenylyl cyclase activities. When other G protein alpha subunits were tested under similar experimental conditions, all three forms of alpha 1 and alpha o1 were able to potentiate the fMLP response to various extents, whereas alpha q and alpha t slightly inhibited the fMLP response. The alpha subunit-mediated potentiation of the type II adenylyl cyclase response appears to reflect a productive coupling between alpha subunits and the fMLP receptor, because such enhancements were not seen with the constitutively activated alpha subunit mutants. Coexpression of the constitutively activated mutants of alpha z, alpha q, alpha 01, and alpha i1-3 neither enhanced nor inhibited the fMLP-stimulated cAMP accumulation. These results indicated that the observed enhancement of type II adenylyl cyclase responses was dependent on the ability of the wild-type alpha subunits to functionally interact with the fMLP receptor and that the fMLP receptor can couple to Gi1-3, Gz, and Go1 but not to Gs, Gq, or Gt.
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PMID:Stimulation of type II adenylyl cyclase by chemoattractant formyl peptide and C5a receptors. 772 45