Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experiments in inbred strains of normotensive and hypertensive rats have clearly demonstrated circadian rhythms in blood pressure and heart rate. Pre- and postsynaptic signal transduction processes in vitro can, but need not, vary with circadian time, greatly depending on the strain of rats investigated. These data highlight the notion of a strain-dependent, and thus genetic, regulation of the cardiovascular system. Obviously, circadian rhythms in blood pressure cannot be explained by single biochemical parameters, but results from both in vitro and in vivo studies give first evidence that the vascular nitric oxide-cGMP system may be involved in the circadian regulation of blood pressure in WKY and SHR rats. In secondary hypertensive TGR and in their normotensive controls, SPRD, the guanylyl cyclase system does not seem to play a role in circadian blood pressure regulation. In neither of the four strains studied did aortic adenylyl cyclase show any time-dependent variation. Because vascular tissue was taken from the thoracic aorta of the rats, a contribution of adenylyl cyclase to circadian blood pressure regulation in small resistance arteries cannot be ruled out. Further studies in different parts of the vascular tree are needed to definitely answer that question. No data are available on time-dependent variation in the activity of phospholipase C, the second messenger pathway of vascular alpha-adrenoceptors and angiotensin II AT1-receptors, both of which mediate vasoconstriction. Future research into this system will be helpful in identifying mechanisms involved in blood pressure regulation in SPRD and TGR.
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PMID:Signal transduction in animal models of normotension and hypertension. 885 34

We investigated the signaling pathways modulating histamine- and prostaglandin F2 alpha (PGF2 alpha)-induced contractions of human chorionic vasculature. Neomycin, a phospholipase C (PLC) inhibitor, attenuated PGF2 alpha and histamine contractile responses 40 and 60%, respectively. AIF4-, a G protein stimulant, induced a strong contraction alone but blocked histamine- and PGF2 alpha-induced contractions. Staurosporine (100 nM), a protein kinase C (PKC) inhibitor, attenuated the PGF2 alpha-dependent contractions by 50% but did not affect the histamine response. However, higher nonspecific inhibitory concentrations of staurosporine (1-2 microM) abolished histamine and PGF2 alpha contractile responses, presumably by inhibiting other protein kinases. Although, the PKC phorbol 12-myristate 13-acetate (PMA) did not affect basal tension or PGF2 alpha-dependent contractions, the histamine response was attenuated by 30%. Sodium nitroprusside (SNP), a guanylyl cyclase stimulant, strongly attenuated histamine- and PGF2 alpha-induced contractions. Tension increases were similarly attenuated by forskolin and isobutylmethylxanthine (IBMX), which increase intracellular cyclic AMP. In vessel rings prelabeled with [3H]myoinositol, PGF2 alpha and histamine increased [3H]inositol phosphate (IP) production 400 and 100%, respectively, indicating that PLC is stimulated by both agonists. Neomycin inhibited histamine- and PGF2 alpha-induced increases in [3H]IP production 60 and 40%, respectively. Staurosporine (0.1-1 microM) and PMA did not affect histamine- or PGF2 alpha-stimulated IP production. AIF4-alone increased IP production but blocked histamine- and PGF(2 alpha)-dependent IP increases. These observations suggest that at least part of the contractile responses due to PGF2 alpha and histamine are associated with stimulation of PLC through an AIF4(-)-sensitive G protein. The role of PKC is variable, because PGF2 alpha but not histamine tension responses were attenuated by PKC inhibition. In addition, therapeutic agents that increase cyclic AMP and cyclic GMP attenuated histamine- and PGF2 alpha-induced contractions in human chorionic vasculature, although histamine responses were relatively more sensitive to these agents.
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PMID:Mechanisms of prostaglandin F2 alpha and histamine-induced contractions in human chorionic vasculature. 887 81

We conducted studies to investigate the nature and underlying mechanisms of the vascular effects of rutaecarpine (Rut), an alkaloid isolated from the Chinese herbal drug Evodia rutaecarpa. By using largely the effects on phenylephrine (PE)-induced contraction in the isolated rat aorta as the experimental index and by comparison with several known vascular muscle relaxants such as acetylcholine (ACh), histamine, and A23187, Rut relaxed PE-precontracted aorta in concentration-(10(-7)-10(-4) M) and endothelium-dependent manners. Studies with appropriate antagonists indicated that this was coupled to nitric oxide (NO) and guanylyl cyclase. Extracellular Ca2+ removal and treatment with the intracellular Ca2+ antagonist, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), suggested that influx of extracellular Ca2+ was the major factor contributing to the action of Rut. Pertussis toxin suppressed the relaxation potency of histamine but had no effects on the actions of Rut. NaF, the G proteins activator, attenuated the actions of ACh, but only minimally affected Na-NP, A23187, and Rut. 1-[6-{[17 beta-3-methoxyestra-1,2,3(10)-trien-17-yl]amino} hexyl]-1H-pyrrole-2,5-dione (U73122), the phospholipase C inhibitor, again suppressed the actions of ACh but had few effects on A23187 and Rut. Taken together, these results suggest that these vasorelaxants had different cellular mechanisms and that neither pertussis toxin-sensitive Gi protein, other G proteins, nor phospholipase C activation was involved in the cellular response to rutaecarpine.
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PMID:Studies of the cellular mechanisms underlying the vasorelaxant effects of rutaecarpine, a bioactive component extracted from an herbal drug. 915 59

The chemoattractant cAMP induces directed cell locomotion in Dictyostelium cells. Several second messenger pathways are activated upon binding of cAMP to G-protein-coupled receptors, including adenylyl cyclase, guanylyl cyclase, phospholipase C, and the opening of plasma membrane Ca2+ channels. These second messenger responses are unaltered in many chemotactic mutants, except for the cGMP response. Activation of guanylyl cyclase depends on G-proteins and is regulated by a cGMP-binding protein in a complex manner. This cGMP-binding protein also mediates intracellular functions of cGMP to activate a PKC-related kinase that phosphorylates myosin II heavy chain, thereby allowing myosin filaments to rearrange during cell movement.
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PMID:cGMP as second messenger during Dictyostelium chemotaxis. 924 16

Atrial natriuretic peptide (ANP) regulates a variety of physiological parameters, including the blood pressure and intravascular volume, by interacting with its receptors present on the plasma membrane. ANP receptors are of three subtypes: ANP-A, -B and -C receptors. ANP-A and ANP-B receptors are guanylyl cyclase receptors, whereas ANP-C receptors are coupled to adenylyl cyclase inhibition or phospholipase C activation through inhibitory guanine nucleotide-regulating protein. Unlike other G protein-coupled receptors, ANP-C receptors have a single transmembrane domain and a short cytoplasmic domain of 37 amino acids, the cytoplasmic domain has a structural specificity like those of other single-transmembrane-domain receptors and 37 amino-acid cytoplasmic domain peptide is able to exert is inhibitory effect on adenylyl cyclase. The activation of ANP-C receptor by C-ANP(4-23) (a ring-deleted peptide of ANP) and C-type natriuretic peptide inhibits the mitogen-activated protein kinase activity stimulated by endothelin-3, platelet-derived growth factor and phorbol-12 myristate 13-acetate. C-ANP also inhibits mitogen-induced stimulation of DNA synthesis, indicating that the ANP-C receptor plays a role in cell proliferation through an inhibition of mitogen-activated protein kinase and suggesting that the ANP-C receptor might also be coupled to other signal transduction mechanism(s) or that there might be an interaction of the ANP-C receptor with some other signalling pathways. ANP receptor binding is decreased in most organs in hypertensive subjects and hypertensive animals. This decrease is consistent with there being fewer guanylyl cyclase-coupled receptors in the kidney and vasculature and selective inhibition of the ANP-C receptor in the thymus and spleen. Platelet ANP-C receptors are decreased in number in hypertensive patients and spontaneously hypertensive rats. ANP-A, -B and -C receptors are decreased in number in deoxycorticosterone acetate-salt-treated kidneys and vasculature; however, the responsiveness of adenylyl cyclase to ANP is augmented in the vasculature and heart and is attenuated completely in platelets. These alterations in ANP receptor subtypes may be related to the pathophysiology of hypertension. Several hormones such as angiotensin II, ANP and catecholamines, the levels of which are increased in hypertension, downregulate or upregulate ANP-C receptors and ANP-C receptor-mediated inhibition of adenylyl cyclase. It can be suggested that the antihypertensive action of several types of drugs such as angiotensin converting enzyme inhibitors, angiotensin type 1 receptor antagonists and beta2-adrenergic antagonists may partly be attributed to their ability to modulate the expression and function of the ANP-C receptor.
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PMID:Atrial natriuretic peptide-C receptor and membrane signalling in hypertension. 928 Feb 3

Pranidipine, a new calcium channel blocker, prolonged endothelium-dependent relaxation induced by acetylcholine in an aortic ring preparation, contracted with prostaglandin F2alpha. This action was not shared by amlodipine. The effect was not modified by indomethacin, suggesting that the action of pranidipine does not involve prostanoid metabolism. N(G)-nitro-L-arginine completely prevented the action of Pranidipine. The drug affected neither nitric oxide (NO) synthase activity nor the level of cyclic GMP in the vessel. Pranidipine did not affect the sensitivity of the contractile proteins to calcium. Pranidipine also did not alter cyclic GMP-induced relaxation in alpha-toxin-skinned vascular preparations. Pranidipine also prolonged glyceryl trinitrate-induced relaxation in the endothelium denuded rat aorta. Furthermore, pranidipine enhanced relaxation of the aorta induced by glyceryl trinitrate even in the presence of methylene blue, a guanylyl cyclase inhibitor. This action was not modified by iberiotoxin or by charybdotoxin, two inhibitors of the calcium-activated potassium channel. The results strongly suggest that pranidipine enhances cyclic GMP-independent NO-induced relaxation of smooth muscle by a mechanism other than through NO-induced hyperpolarization. These effects were in direct contrast to amlodipine, another new 1,4-dihydropyridine calcium antagonist.
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PMID:Pranidipine, a new 1,4-dihydropyridine calcium channel blocker, enhances cyclic GMP-independent nitric oxide-induced relaxation of the rat aorta. 954 18

Exposure of Clone 9 cells, a nontransformed rat liver cell line expressing only the Glutl glucose transporter isoform, to the guanylyl cyclase inhibitor LY-83583 was found to stimulate the rate of glucose transport (approximately 7- to 8-fold in 1 h). A similar response to LY-83583 was found in NIH 3T3 fibroblasts, 3T3-L1 pre-adipocytes, and C2C12 myoblasts. Neither the rate of glucose transport in cells under control conditions nor the effect of LY-83583 on glucose transport was altered by 10, 50, or 100 microM 8-bromo-cGMP or by addition of cGMP phosphodiesterase inhibitors, zaprinast, or dipyridamole suggesting that glucose transport and the response to LY-83583 is independent of cGMP levels. In addition, the effect of LY-83583 on glucose transport was not mediated by inhibition of oxidative phosphorylation, since exposure to the agent resulted in no increase in lactate production. Incubation of Clone 9 cells in the presence of the phospholipase C inhibitor U73122, however, attenuated the glucose transport response to LY-83583. Moreover, exposure to LY-83583 resulted in a rise in cell diacylglycerol content, and preincubation with U73122 significantly diminished this rise as well as the glucose transport response to LY-83583. The stimulatory effect of LY-83583 on glucose transport was significantly blocked by thapsigargin. Down-regulation of protein kinase C activity, resulting from 24 h pre-incubation in the presence of 160 nM phorbol-12-myristate 13-acetate, did not attenuate the glucose transport response to LY-83583. It is concluded that the stimulation of glucose transport in response to LY-83583 is independent of changes in cGMP levels, is not mediated by inhibition of oxidative phosphorylation, and is mediated, at least in part, through stimulation of the phospholipase C pathway.
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PMID:LY-83583 stimulates glucose transporter-1-mediated glucose transport independent of changes in cGMP levels. 1006 58

We have shown recently that the 37-amino acid intracellular domain of the single-transmembrane, natriuretic peptide clearance receptor, NPR-C, which is devoid of kinase and guanylyl cyclase activities, activates selectively Gi1 and Gi2 in gastric and tenia coli smooth muscle. In this study, we have used synthetic peptide fragments of the N-terminal, C-terminal, and middle regions of the cytoplasmic domain of NPR-C to identify the G protein-activating sequence. A 17-amino acid peptide of the middle region (Arg469-Arg485), denoted Peptide 4, which possesses two N-terminal arginine residues and a C-terminal B-B-X-X-B motif (where B and X are basic and non-basic residues, respectively) bound selectively to Gi1 and Gi2, activated phospholipase C-beta3 via the betagamma subunits, inhibited adenylyl cyclase, and induced smooth muscle contraction, in similar fashion to the selective NPR-C ligand, cANP4-23. A similar sequence (Peptide 3), but with a partial C-terminal motif, had minimal activity. Sequences which possessed either the N-terminal basic residues (Peptide 1) or the C-terminal B-B-X-X-B motif (Peptide 2) were inactive. Peptide 2, however, inhibited G protein activation and cellular responses mediated by the stimulatory Peptide 4 and by cANP4-23, suggesting that the B-B-X-X-B motif mediated binding but not activation of G protein, thus causing Peptide 2 to act as a competitive inhibitor of G protein activation.
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PMID:Identification of the G protein-activating domain of the natriuretic peptide clearance receptor (NPR-C). 1036 94

The heterotrimeric G protein, G2, from the eukaryotic organism Dictyostelium discoideum participates in signal transduction pathways which are essential to Dictyostelium's developmental life cycle. G2 is activated by cell surface cAMP receptors and in turn is required for the activation of a host of effectors, including adenylyl cyclase, guanylyl cyclase, and phospholipase C. Myristoylation of G protein alpha-subunits is known to affect alpha-subunit association with the beta gamma subunits and membrane localization. The putative site for N-terminal myristoylation of G alpha 2 was mutated from Gly to Ala (G2A) and expressed in the g alpha 2-null cell line, MYC2. Transformants expressing G alpha 2-G2A exhibit physiological and biochemical changes from wild-type cells. G alpha 2-G2A expressing cells fail to rescue the aggregation-minus phenotype of MYC2 cells on developmental agar plates. G alpha 2-G2A expressing cells are also not chemotactic to cAMP in a standard drop assay. G alpha 2-WT is found in both the pellet and supernatant fractions following lysis of the cells. G alpha 2-G2A however is found almost exclusively in the lysate supernatant. G alpha 2 is radiolabeled upon incubation of cells in [3H]myristate, while G alpha 2-G2A is not labeled. Examination of activation of the effectors adenylyl cyclase and guanylyl cyclase reveals that G alpha 2-G2A expressing cells partially activate adenylyl cyclase but show no cAMP-stimulation of guanylyl cyclase. The physiological deviations from wild-type can be explained by the variations in effector activation, possibly due to improper localization of the non-myristoylated G alpha 2-G2A to the cytosol.
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PMID:Aggregation of Dictyostelium discoideum is dependent on myristoylation and membrane localization of the G protein alpha-subunit, G alpha 2. 1040 98

Cell injury frequently occurs in the setting of tissue destruction and inflammation and is associated with a rise in intracellular calcium (Cai) and increased NO production. The mechanisms that trigger rises in Cai and NO during cell injury are not fully defined, but they may involve activation of G protein-coupled receptors for substances such as bradykinin, Ang II, thromboxane, and thrombin. These receptors act through G proteins from different families that have distinct functions. Receptors for bradykinin and Ang II act through members of the G alpha i and G alpha q families, whereas receptors for thrombin and thromboxane act through members of the G alpha i, G alpha q, and G alpha 12/13 families. These G proteins cooperate to regulate Cai and NO in epithelial cells through distinct mechanisms. In a number of experimental settings, activators of the adenylyl cyclase system reduce the severity of cell injury. To understand the mechanisms by which G protein-dependent signaling systems may contribute to cell injury and to define the role of adenylyl cyclase in ameliorating cell injury, the effects of adenylyl cyclase on bradykinin-stimulated Ca influx and NO in cultured renal epithelial cells that stably overexpress G alpha q and G alpha 13 were studied. This system allowed for the separation of different components of the signals initiated by receptors for thromboxane and thrombin. G alpha 13 increased bradykinin-stimulated Ca influx by a mechanism that depends on NO and cGMP. The increased Ca influx was blocked by inhibitors of NO synthase and guanylyl cyclase and by activation of adenylyl cyclase. NO production was inhibited by activators of cAMP-dependent protein kinase, which indicated that cAMP blocks Ca influx by inhibiting NO production. Expression of G alpha q, the G protein that regulates phospholipase C, also increased bradykinin-stimulated Ca influx, but by an NO, cGMP-independent mechanism that was insensitive to inhibition by adenylyl cyclase. The authors conclude that Ca influx is modulated by NO-dependent and independent mechanisms, and that to the extent that increased NO production contributes to increased Ca influx and cell injury, cell injury may be reduced by agents that activate adenylyl cyclase.
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PMID:Inhibition of nitric oxide synthase activity and nitric oxide-dependent calcium influx in renal epithelial cells by cyclic adenosine monophosphate: implications for cell injury. 1049 85


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