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Query: UNIPROT:P19086 (Galphaz)
 110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

alpha 1-Adrenergic receptors (ARs) are members of the G protein-coupled receptor superfamily. alpha 1-AR subtypes mediate the effects of the sympathetic nervous system, especially those involved in cardiac homeostasis. To investigate signal transduction by a novel subtype (alpha 1D), which we recently cloned, and to compare it with that by the previously characterized alpha 1B-AR, we assessed the ability of each subtype to activate polyphosphoinositide (PI) metabolism, cAMP accumulation, and arachidonic acid release in Chinese hamster ovary (CHO) and COS-1 cells expressing these subtypes after stable or transient transfection, respectively. In COS-1 and CHO cells, both the alpha 1D- and alpha 1B-AR were found to couple to PI hydrolysis through a pertussis toxin-insensitive G protein. Both alpha 1-AR subtypes also increased intracellular cAMP by an indirect mechanism, although this effect was observed only in COS-1 cells and not in CHO cells. Interestingly, alpha 1-AR-stimulated arachidonic acid release was also demonstrated for both subtypes in COS-1 cells. This release was mediated through phospholipase A2 activation and involved a pertussis toxin-sensitive G protein. alpha 1-AR-stimulated arachidonic acid release was dependent upon extracellular calcium and was inhibited by 1 microM nifedipine. Inhibitors of protein kinase C, phospholipase C, and diacylglycerol lipase did not alter alpha 1-AR-stimulated release of arachidonic acid. These findings indicate that in COS-1 cells alpha 1-AR-stimulated arachidonic acid release is most likely coupled to dihydropyridine-sensitive L-type calcium channels via a pertussis toxin-sensitive G protein. The influx of extracellular calcium then stimulates phospholipase A2 to release arachidonic acid. alpha 1-AR-stimulated arachidonic acid release could also be demonstrated in CHO cells and was pertussis toxin sensitive but nifedipine insensitive. These cells were also unresponsive to Bay K8644, indicating a lack of voltage-sensitive calcium channels in CHO cells. Nevertheless, alpha 1-AR activation increased intracellular Ca2+ levels, as assessed by fura-2 fluorescence studies. Neomycin blocked both alpha 1-AR-stimulated PI hydrolysis and increases in intracellular Ca2+ levels but did not inhibit the increase in arachidonic acid release. Taken together, these data indicate that in CHO cells alpha 1-ARs can couple directly to phospholipase A2 activation via a pertussis toxin-sensitive pathway. Thus, in these model systems we demonstrate for the first time that a single alpha 1-AR subtype can activate multiple distinct signal transduction pathways, in which receptor-effector coupling is modulated by distinct G proteins.
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PMID:Coupling of expressed alpha 1B- and alpha 1D-adrenergic receptor to multiple signaling pathways is both G protein and cell type specific. 823 29

We have shown that in bovine iris sphincter membranes G proteins are involved in coupling muscarinic-, PGF2 alpha-, endothelin- and platelet-activating factor receptors to the activation of phospholipase A2 and the release of arachidonic acid. GTP gamma S and GTP gamma S plus carbachol stimulated arachidonic acid release in the membranes in a dose- and time-dependent manner. Nucleotide stimulation was specific to GTP gamma S, since GDP, GDP beta S and ATP had no effect. The stimulatory effect of GTP gamma S plus carbachol was blocked by atropine and it required the presence of physiological concentrations of Ca2-. AIF4-, which bypasses the receptor and directly activates the G protein, induced arachidonic acid liberation in the intact iris sphincter, but was ineffective in the membranes. Addition of GTP gamma S plus carbachol to sphincter muscle membranes prelabeled with [3H]inositol or 3H-arachidonic acid resulted in the formation of lysophosphatidylinositol and the liberation of arachidonic acid, thus suggesting the involvement of phospholipase A2. In vitro treatment of the iris membranes with pertussis toxic inhibited arachidonic acid release by the agonists. This is in contrast to the pertussis toxin-insensitive G protein that activates phospholipase C in this tissue (22). These data demonstrate that in the iris sphincter a G protein is involved in the step between receptor activation and the activation of phospholipase A2, and that arachidonic acid release in this tissue is mediated by a pertussis-toxin-sensitive G protein-coupled phospholipase A2. Thus, GTP can regulate arachidonic acid release and its subsequent conversion into eicosanoids by stimulating its formation.
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PMID:Involvement of a pertussis toxin-sensitive G protein-coupled phospholipase A2 in agonist-stimulated arachidonic acid release in membranes isolated from bovine iris sphincter smooth muscle. 851 May 60

We previously showed that acetylcholine (ACh) stimulates production of prostacyclin, measured as immunoreactive 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in coronary endothelial cells (CEC) of rabbit heart by increasing influx of extracellular Ca2+ through a receptor-operated Ca2+ channel and by activating a pertussis toxin-insensitive G protein. The purposes of this study were to elucidate the type of phospholipase A2 (PLA2) involved in 6-keto-PGF1 alpha production and the mechanism(s) by which ACh activates PLA2 in cultured CEC. In CEC transiently transfected with cytosolic PLA2 but not secretory PLA2 antisense oligonucleotide, ACh failed to increase 6-keto-PGF1 alpha; this was prevented by cotransfection with cPLA2 sense oligonucleotide. ACh increased production of prostacyclin and increased protein kinase C (PKC) activity. The PKC inhibitor calphostin C attenuated the ACh-induced increase in PKC activity but not 6-keto-PGF1 alpha production. Phorbol-12-myristate-13-acetate and phorbol-12, 13-dibutyrate increased PKC activity but failed to alter 6-keto-PGF1 alpha production. ACh enhanced the activity of cPLA2 and p42 mitogen-activated protein kinase (MAPK) in cell lysate prepared from CEC. ACh also caused phosphorylation of p42 MAPK and cPLA2, which was inhibited by AG126 ([alpha-cyano-(3-hydroxy-4-nitro)cinnamonitrile]), a tyrosine kinase inhibitor known to decrease MAPK activity. In addition, ACh stimulated translocation of cPLA2 from cytosol to nuclear envelope; the translocation of cPLA2 was prevented by removal of extracellular calcium but not by AG126 treatment. Okadaic acid, a protein phosphatase inhibitor, increased cPLA2 activity in cell lysate prepared from CEC but did not alter basal 6-keto-PGF1 alpha production in intact CEC; however, ACh-induced 6-keto-PGF1 alpha was enhanced by okadaic acid. These data suggest that ACh stimulates prostacyclin synthesis by activation of cPLA2 in a PKC-independent mechanism and that both cPLA2 translocation to nuclear envelope and phosphorylation by MAPK are required for ACh-induced 6-keto-PGF1 alpha synthesis in CEC.
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PMID:Involvement of mitogen-activated protein kinase and translocation of cytosolic phospholipase A2 to the nuclear envelope in acetylcholine-induced prostacyclin synthesis in rabbit coronary endothelial cells. 891 45

We investigated the mechanisms underlying bradykinin (BK)-induced rise in intracellular Ca++ concentration [Ca++]i and insulin secretion using clonal beta cell line RINm5F. Incubation with a range of concentrations of BK increased in concentration-dependent manners both insulin secretion (BK of 10 nM to 10 microM) and [Ca++]i (BK of 100 nM to 100 microM). In Ca++-containing medium, BK (1 microM) induced a biphasic [Ca++]i rise, which was characterized by a Ca++ peak and a sustained Ca++ phase. In the Ca++-free medium, BK failed to increase insulin secretion and induced only a Ca++ peak without the sustained Ca++ phase. Thapsigargin (1 microM), an inhibitor of the Ca++ pump in the endoplasmic reticulum, abolished the Ca++ peak and the sustained phase. Nimodipine (1 microM), a voltage-dependent Ca++ channel blocker, abolished the BK-induced sustained Ca++ phase and inhibited BK-induced insulin release. The BK1 receptor agonist des-Arg9-BK (1 microM) did not change either [Ca++]i or insulin secretion. Both the BK-induced insulin secretion and rise in [Ca++]i were inhibited by a selective BK2 receptor antagonist, HOE 140 (3.3-100 nM), in concentration-dependent manners but were not by a BK1 receptor antagonist des-Arg9,Leu8-BK (1 microM). Pretreatment with pertussis toxin (0.1 microg/ml) did not block the BK-induced insulin secretion or increase in [Ca++]i. U-73122 (4, 6 and 8 microM), a phospholipase C inhibitor, antagonized both the BK-induced insulin secretion and the increase in [Ca++]i in a concentration-dependent and parallel manner. BK increased intracellular concentrations of inositol-1,4,5-trisphosphate (IP3). Neither (p-amylcinnamoyl)anthranilic acid (100 microM), a phospholipase A2 inhibitor, nor N(G)-nitro-L-arginine methylester (100 microM), a nitric oxide synthase inhibitor, inhibited these effects of BK. Taken together, these findings suggested that in beta cells, BK activates BK2 receptors, which, in turn, activate a pertussis toxin-insensitive G protein. The G protein couples to phospholipase C, which promotes the formation of IP3 and diacylglycerol. IP3 releases [Ca++]i from the intracellular Ca++ store, probably the endoplasmic reticulum, which triggers Ca++ influx via voltage-dependent Ca++ channels and thus increases insulin secretion.
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PMID:Mechanisms of bradykinin-induced insulin secretion in clonal beta cell line RINm5F. 931 32

Macrophages exposed to receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) demonstrate increased DNA synthesis and cell division. In the current study, we have probed the role of cytosolic phospholipase A(2) (cPLA(2)) activity in the cellular response to alpha(2)M*. Ligation of the alpha(2)M* signaling receptor by alpha(2)M*, or its receptor binding fragment, increased cPLA(2) activity 2-3-fold in a concentration and time-dependent manner. This activation required a pertussis toxin-insensitive G protein. Cellular binding of alpha(2)M* also induced transient translocation of cPLA(2) activity to nuclei and membrane fractions. Inhibition of protein kinase C activity or chelation of Ca(2+) inhibited alpha(2)M*-induced increased cPLA(2) activity. Binding of alpha(2)M* to macrophages, moreover, increased phosphorylation of MEK 1/2, ERK 1/2, p38 MAPK, and JNK. Incubation of macrophages with inhibitors of MEK 1/2 or p38 MAPK before stimulation with alpha(2)M* profoundly decreased phosphorylation of MAPKs, blocking cPLA(2) activation. alpha(2)M*-induced increase in [(3)H]thymidine uptake and cell proliferation was completely abolished if activation of cPLA(2) was prevented. The response of macrophages to alpha(2)M* requires transcription factors nuclear factor kappaB, and cAMP-responsive element-binding protein as well as expression of the proto-oncogenes c-fos and c-myc. These studies indicate that the activation of cPLA(2) plays a crucial role in alpha(2)M*-induced mitogenesis and cell proliferation.
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PMID:Regulation of cytosolic phospholipase A2 activity in macrophages stimulated with receptor-recognized forms of alpha 2-macroglobulin: role in mitogenesis and cell proliferation. 1173 96