Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of thrombin and GTP gamma S on the hydrolysis of phosphoinositides by membrane-associated phospholipase C (PLC) from human platelets were examined with endogenous [3H]inositol-labeled membranes or with lipid vesicles containing either [3H]phosphatidylinositol or [3H]phosphatidylinositol 4,5-bisphosphate. GTP gamma S (1 microM) or thrombin (1 unit/mL) did not stimulate release of inositol trisphosphate (IP3), inositol bisphosphate (IP2), or inositol phosphate (IP) from [3H]inositol-labeled membranes. IP2 and IP3, but not IP, from [3H]inositol-labeled membranes were, however, stimulated 3-fold by GTP gamma S (1 microM) plus thrombin (1 unit/mL). A higher concentration of GTP gamma S (100 microM) alone also stimulated IP2 and IP3, but not IP, release. In the presence of 1 mM calcium, release of IP2 and IP3 was increased 6-fold over basal levels; however, formation of IP was not observed. At submicromolar calcium concentration, hydrolysis of exogenous phosphatidylinositol 4,5-bisphosphate (PIP2) by platelet membrane associated PLC was also markedly enhanced by GTP gamma S (100 microM) or GTP gamma S (1 microM) plus thrombin (1 unit/mL). Under identical conditions, exogenous phosphatidylinositol (PI) was not hydrolyzed. The same substrate specificity was observed when the membrane-associated PLC was activated with 1 mM calcium. Thrombin-induced hydrolysis of PIP2 was inhibited by treatment of the membranes with pertussis toxin or pretreatment of intact platelets with 12-O-tetradecanoyl-13-acetate (TPA) prior to preparation of membranes. Pertussis toxin did not inhibit GTP gamma S (100 microM) or calcium (1 mM) dependent PIP2 breakdown, while TPA inhibited GTP gamma S-dependent but not calcium-dependent phospholipase C activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma membrane associated phospholipase C from human platelets: synergistic stimulation of phosphatidylinositol 4,5-bisphosphate hydrolysis by thrombin and guanosine 5'-O-(3-thiotriphosphate). 253 64

The properties of thromboxane A2 (TXA2) receptors were examined in 1321N1 human astrocytoma cells. 9,11-Epithio-11,12-methanothromboxane A2 (STA2), a stable analogue of TXA2, stimulated the accumulation of inositol phosphates (IPs) with an EC50 of about 50 nM. The STA2-induced accumulation of IPs was inhibited concentration dependently by ONO3708, a TXA2 receptor antagonist, with an inhibition constant (Ki) of about 10 nM. Inositol trisphosphate (IP3) was accumulated more rapidly than inositol bisphosphate (IP2) in response to STA2. HPLC analysis indicated that inositol 1,4,5-trisphosphate accumulated in the presence of STA2. STA2 alone had no effect on the accumulation of IPs in membrane preparations but it potentiated the accumulation induced by GTP gamma S. [3H]SQ29548, a TXA2 receptor antagonist, bound specifically to TXA2 receptors, expressing a single binding site with a dissociation constant (Kd) of 10.9 nM. The competition curve for STA2 inhibition of [3H]SQ29548 binding was shifted to the right and was steeper in the presence of GTP gamma S. Pertussis toxin (IAP) elicited ADP-ribosylation of 41KD protein but had no effect on the sensitivity to GTP of the STA2 inhibition of SQ29548 binding or of STA2-induced accumulation of IPs. It is concluded from these results that the stimulation of TXA2 receptors results in activation of phospholipase C via a GTP binding protein and that the protein is not a substrate for IAP.
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PMID:Thromboxane A2 activates phospholipase C in astrocytoma cells via pertussis toxin-insensitive G-protein. 254 56

We demonstrated previously that alpha-1 adrenergic catecholamines modulate cardiac automaticity in a manner that is dependent upon the function of a pertussis toxin sensitive guanine nucleotide binding protein (G protein). Furthermore, we demonstrated that alpha-1 adrenergic receptor stimulation promotes the accumulation of inositol monophosphate (IP1). In the present study we used high-pressure liquid chromatography to resolve individual inositol phosphate isomers formed in norepinephrine-stimulated cultured rat ventricular myocytes. Norepinephrine stimulated a rapid, transient increase in 1,4,5-inositol trisphosphate (1,4,5-IP3) which was followed by slower, sustained increases in 1,3,4-IP3, inositol bisphosphate (IP2) and IP1. IP1 was composed of two major isomers with retention times characteristic of 1-IP1 and 4-IP1. 4-IP1 was the predominant IP1 isomer formed during stimulation with norepinephrine suggesting that the polyphosphoinositides rather than phosphatidylinositol are the principal targets of norepinephrine-stimulated phospholipase C activity in the heart. This was confirmed in studies performed on myocyte membranes which demonstrated proportionately greater IP2 and IP3 (relative to IP1) accumulation in response to norepinephrine. G protein regulation of alpha-1 adrenergic-dependent inositol phospholipid hydrolysis also was examined. In myocyte membranes, guanosine-5'-0-(3-thiotriphosphate) induced the accumulation of IP2 and IP3 and was required for the stimulatory effect of norepinephrine. This response was not impaired after pretreatment with pertussis toxin. These results indicate that the myocyte alpha-1 adrenergic receptor is coupled to a polyphosphoinositide-specific phospholipase C by a pertussis toxin insensitive G protein and suggest that under certain conditions IP3 may serve an important role in alpha-1 adrenergic modulation of cardiac function.
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PMID:Alpha-1 adrenergic stimulation of 1,4,5-inositol trisphosphate formation in ventricular myocytes. 255 Jun 17

We have investigated the influence of the neural cell adhesion molecules L1 and N-CAM on second messenger systems using a PC12 rat pheochromocytoma cell line as a model and triggering cell surface receptors by specific antibody binding. Antibodies directed against L1 and N-CAM, but not against other cell surface components, reduce intracellular levels of the inositol phosphates IP2 and IP3, while intracellular levels of cAMP are unaffected. Antibodies against L1 and N-CAM also reduce intracellular pH and increase intracellular Ca2+ by opening Ca2+ channels in a pertussis toxin-inhibitable manner, suggesting the involvement of a G protein in the signal transduction process. Cross-linking of the adhesion molecules on the surface membrane is not required for the effects to occur. Furthermore, adhesion of single PC12 cells to each other elicits effects on intracellular pH and Ca2+ similar to those seen after application, underscoring the physiological significance of the observed changes.
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PMID:Neural cell adhesion molecules influence second messenger systems. 255 59

In previous studies, we showed that cardiac muscarinic receptors (M2) are composed of two subgroups, M2 alpha and M2 beta, with different affinities for agonists and that the M2 alpha subgroup is coupled with inhibition of adenylate cyclase. We now studied which subgroup was responsible for the formation of inositol mono- (IP), bis- (IP2), tris- (IP3) and tetrakis- (IP4) phosphates in guinea pig heart. Carbachol (1 mM) significantly stimulated the formation of all four IPs in [3H]myoinositol-preloaded slices of guinea-pig ventricles. Acetylcholine (1 mM) also stimulated the formation of IP2, IP3 and IP4. However, oxotremorine (1 mM) only slightly stimulated the formation of IP2, and pilocarpine did not stimulate the formation of any IP. The pED50 values of carbachol for IP2 and IP3 formation were 3.76 and 4.23, respectively, which coincided with the pKd values of the low-affinity agonist binding site (L site) measured by competition of carbachol with [3H]quinuclidinyl benzilate [( 3H]QNB) binding while the pKd value for inhibition of adenylate cyclase coincided with the pKd value of the high-affinity agonist binding site (H site). Treatment of animals with pertussis toxin decreased the formation of IP2 and IP3 by carbachol to 66 and 54%, respectively, but resulted in complete inhibition of adenylate cyclase. These results suggested that muscarinic stimulation of the formation of IPs was manifested through a different receptor subgroup (M2 beta) and GTP binding protein different from those for inhibition of adenylate cyclase.
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PMID:The H-L subgroup of guinea-pig cardiac M2 receptors (M2 beta) regulates inositol phosphate formation. 258 43

To investigate whether guanosine triphosphate-binding proteins (G proteins) are involved in T cell activation, tests were made of the effect of pertussis toxin, cholera toxin, guanosine 5'-(3-O-thio)-triphosphate, and fluoride ions on interleukin 2 (IL-2) synthesis in Jurkat cells. It was found: 1) that pertussis toxin interferes with the first pathway of T cell activation insofar as it can substitute for phytohemagglutinin or monoclonal antibodies directed against the CD3 surface proteins, suggesting that a G protein serves as transducer for signals via the T cell receptor-CD3 complex; and 2) that fluoride ions induce the release of diacylglycerol (DAG) from [3H] arachidonic acid or [3H]oleic acid-prelabeled cells. In [3H]inositol or 32P-prelabeled cells, the increase in DAG production was also found to be accompanied by a 280% increase of intracellular inositol phosphate (IP), without significant modification of IP2 and IP3. These results suggest that a G protein controls the activity of a phospholipase C in Jurkat cells that upon stimulation releases DAG but not IP3. Inasmuch as DAG, like the phorbol ester tetradecanoyl phorbol acetate, activates protein kinase C, it suggests that a G protein is also involved in the transduction of the second signal for lymphocyte activation. Fluoride ions were found to be as effective as tetradecanoyl phorbol acetate to stimulate IL-2 synthesis in Jurkat cells when used in combination with phytohemagglutinin. Finally, cholera toxin and guanosine 5'-(3-O-thio)-triphosphate were found to increase intracellular cyclic adenosine triphosphate and to inhibit IL-2 synthesis. All together these results suggest that several G proteins are involved in the transduction of the two signals necessary for T cell activation as well as in the negative regulation of IL-2 synthesis.
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PMID:Inhibition and activation of interleukin 2 synthesis by direct modification of guanosine triphosphate-binding proteins. 282 88

The plasma-membrane receptors, coupling mechanisms, and effector enzymes that mediate target-cell activation by angiotensin II (AII) have been characterized in rat and bovine adrenal glomerulosa cells. The AII holoreceptor is a glycoprotein of Mr approximately 125,000 under non-denaturing conditions. Photoaffinity labeling of AII receptors with azido-AII derivatives has shown size heterogeneity among the AII binding sites between species and target tissues, with Mr values of 55,000 to 79,000. Such variations in molecular size probably reflect differences in carbohydrate content of the individual receptor sites. The adrenal AII receptor, like that in other tissues, is coupled to the inhibitory guanine nucleotide inhibitory protein (Ni). However, studies with pertussis toxin have shown that stimulation of aldosterone production by AII is not mediated by Ni but by a pertussis-insensitive nucleotide regulatory protein of unidentified nature. Although Ni is not involved in the stimulatory action of AII on steroidogenesis, it does mediate the inhibitory effects of high concentrations of AII upon aldosterone production. The actions of AII on adrenal cortical function are thus regulated by at least two guanine nucleotide regulatory proteins that are selectively activated by increasing AII concentrations. The principal effector enzyme in AII action is phospholipase C, which is rapidly stimulated in rat and bovine glomerulosa after AII receptor activation. AII-induced breakdown of phosphatidylinositol bisphosphate (PIP2) and phosphatidylinositol phosphate (PIP) leads to formation of inositol 1,4,5-trisphosphate (IP3) and inositol 1,4-bisphosphate (IP2). These are metabolized predominantly to inositol-4-monophosphate, which serves as a marker of polyphosphoinositide breakdown, whereas inositol-1-phosphate is largely derived from phosphatidylinositol hydrolysis. The AII-stimulated glomerulosa cell also produces inositol 1,3,4-trisphosphate, a biologically inactive IP3 isomer formed from Ins-1,4,5-trisphosphate via inositol tetrakisphosphate (IP4) during ligand activation in several calcium-dependent target cells. The Ins-1,4,5-P3 formed during AII action binds with high affinity to specific intracellular receptors that have been characterized in the bovine adrenal gland and other AII target tissues, and may represent the sites through which IP3 causes calcium mobilization during the initiation of cellular responses.
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PMID:Angiotensin II receptors and mechanisms of action in adrenal glomerulosa cells. 282 11

The production of inositol phosphates in response to carbachol was studied in rat anterior pituitary tissue prelabelled with [3H]inositol. Carbachol (10 microM) stimulated inositol mono-, bis- and trisphosphate production (IP1, IP2 and IP3) by 360 +/- 49, 338 +/- 49 and 503 +/- 49 (mean +/- SEM, P less than 0.001) percent respectively during a 30 min incubation. Mean basal production was 5.4 +/- 0.3, 4.1 +/- 0.5 and 0.9 +/- 0.3 expressed as a percent of total [3H]inositol lipid for IP, IP2 and IP3 respectively. Stimulated inositol phosphate production was dose dependent and detectable after 5 min. Atropine prevented this stimulation indicating mediation via muscarinic receptors. Removal of extracellular Ca2+ reduced both basal and stimulated total inositol phosphate production by 60% and 56% respectively but did not impair carbachol-induced phosphoinositide hydrolysis per se. Pretreatment of pituitary tissue with either somatostatin (5 micrograms/ml) or pertussis toxin (1 microgram/ml) had no effect on either basal or stimulated inositol phosphate production. These results demonstrate a cholinergic stimulation of phosphatidylinositol bisphosphate (PIP2) hydrolysis in the anterior pituitary which may be important in the action of cholinergic agonists on pituitary hormone secretion.
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PMID:Cholinergic stimulation of phosphoinositide hydrolysis in rat anterior pituitary. 289 24

Binding of chemoattractants to specific cell surface receptors on human polymorphonuclear leukocytes (PMNs) initiates a variety of biologic responses, including directed migration (chemotaxis), release of superoxide anions, and lysosomal enzyme secretion. Chemoattractant receptors belong to a large class of receptors which utilize the hydrolysis of polyphosphoinositides to initiate Ca2+ mobilization and cellular activation. Receptor occupancy leads to phospholipase C-mediated hydrolysis of polyphosphoinositol 4,5-bisphosphate (PIP2) yielding inositol 1,4,5-trisphosphate (IP3) and 1,2 sn-diacylglycerol (DAG). These products synergize to initiate cell activation via calcium mobilization (IP3) and protein kinase C activation (DAG). Pertussis toxin, which ADP-ribosylates and inactivates some GTP binding proteins (G proteins), abolishes all chemoattractant-induced responses, including Ca2+ mobilization, IP3 and DAG production, enzyme secretion, superoxide production and chemotaxis. Direct evidence for chemoattractant receptor: G protein coupling was obtained using PMN membrane preparations which contain a Ca2+-sensitive phospholipase C. Hydrolysis of polyphosphoinositides at resting intracellular Ca2+ levels (100 nm) was only observed when the membranes were stimulated with the chemoattractant N-formyl-methyl-leucyl-phenylalanine (fMet-Leu-Phe) in the presence of GTP. Myeloid cells contain two distinct pertussis toxin substrates of similar molecular weight (40 and 41 kD). The 41 kD substrate resembles Gi, whereas a 40 kD substrate is physically associated with a partially purified fMet-Leu-Phe receptor preparation and may therefore represent a novel G protein involved in chemoattractant-stimulated responses. Metabolism of 1,4,5-IP3 to inositol proceeds via two distinct pathways in PMNs: (1) degradation to 1,4-IP2 and 4-IP1 or (2) conversion to 1,3,4,5-IP4, 1,3,4-IP3, 3,4-IP2 and 3-IP1. Initial formation (0-30 s) of 1,4,5-IP3 and DAG occurs at ambient intracellular Ca2+ levels, whereas formation of 1,3,4-IP3 and a second sustained phase of DAG production (30 s-10 min) require elevated cytosolic Ca2+ influx. The later peak of DAG, which is not derived from phosphoinositides, appears to be required for stimulation of respiratory burst activity. Products formed during activation can feed back to attenuate chemoattractant receptor-mediated stimulation of phospholipase C by uncoupling receptor-G protein-phospholipase C interaction.
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PMID:Signal transduction in cells following binding of chemoattractants to membrane receptors. 290 Nov 61

Vasopressin-induced phosphatidylinositol turnover and mobilization of intracellular Ca2+ was studied using an established smooth muscle cell line (A-10). The cells were subcloned to ensure a monoclonal cell population. The accumulation of inositol mono-, di-, and tris-phosphates (IP1, IP2, and IP3, respectively), and the mobilization of intracellular Ca2+ were dependent on the time of incubation and the concentration of arginine vasopressin (AVP). IP1, IP2, and IP3 were significantly elevated after 15 sec and remained elevated for up to 2 hr. The concentrations of AVP required for half-maximal stimulation of IP1, IP2, and IP3 formation were 2, 12, and 4 nM, respectively. LiCl was required to observe the accumulation of inositol phosphates in response to AVP. Significant 45Ca2+ efflux was observed within 15 sec after exposure to AVP. By employing the vasopressin receptor subtype selective antagonists [d(CH2)5Tyr(Me)AVP, V1; d(CH2)5D-Tyr(Et)VAVP,V1/V2; d(CH2) 5D-IleVAVP,V2] and agonists [AVP, V1/V2; dDAVP, V2; dVDAVP, V2], we found that the vasopressin-induced stimulation of phosphatidylinositol turnover and 45Ca2+ efflux were mediated by receptors of the vascular V1 subtype. Pertussis toxin pretreatment partially inhibited vasopressin-induced phosphatidylinositol turnover. These data demonstrate that activation of V1 receptors of vascular smooth muscle cells resulted in enhanced phosphatidylinositol turnover and mobilization of intracellular Ca2+.
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PMID:Vascular vasopressin receptors mediate phosphatidylinositol turnover and calcium efflux in an established smooth muscle cell line. 301 49


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