Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Single rat hepatocytes microinjected with aequorin show free Ca oscillations when stimulated with Ca(2+)-mobilizing hormones. We show here that an inhibitor of diacylglycerol kinase (R 59 022) and an analogue of native diacylglycerol (diC8) inhibit free Ca oscillations induced by phenylephrine and vasopressin. These results agree with a negative feedback effect of protein kinase C on free Ca oscillations.
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PMID:Effect of perturbing diacylglycerol metabolism on cytosolic free Ca2+ oscillations induced in single hepatocytes. 133 Jun 80

To elucidate the transmembrane signalling processes initiated by fibroblast growth factor (FGF), we have studied the effect of recombinant basic FGF (bFGF) on various early events associated with mitogenesis in Swiss 3T3 fibroblasts. bFGF, at mitogenic concentrations, neither induced Ca2+ mobilization from intracellular stores nor increased the accumulation of inositol phosphates. In contrast, bFGF stimulated the phosphorylation of the Mr 80,000 (80K) cellular protein which is a major substrate of protein kinase C. This effect was potentiated by the diacylglycerol kinase inhibitor R59022. Two-dimensional polyacrylamide gel electrophoresis and phosphopeptide mapping showed that the 80K phosphoproteins generated in response to bFGF, bombesin, and phorbol 12,13-dibutyrate were indistinguishable. Down-regulation of protein kinase C prevented bFGF stimulation of 80K phosphorylation. Other protein kinase C-dependent early events such as transmodulation of the epidermal growth factor receptor, cytoplasmic alkalinization, inhibition of vasopressin induced increase in cytosolic [Ca2+], and enhancement of cAMP accumulation in response to forskolin were also induced by bFGF. Similar results were obtained when bFGF was added to quiescent cultures of tertiary mouse embryo fibroblasts. We conclude that bFGF stimulates protein kinase C through a signal transduction pathway distinct from inositol phospholipid turnover and Ca2+ mobilization.
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PMID:Fibroblast growth factor stimulates protein kinase C in quiescent 3T3 cells without Ca2+ mobilization or inositol phosphate accumulation. 215 12

Studies on BC3H-1 myocytes suggest that the insulin-induced increase in cellular diacylglycerol level mediates the insulin-stimulated glucose transport in these cells (Standaert, M. L., Farese, R. V., Cooper, D. R., and Pollet, R. J. (1988) J. Biol. Chem. 263, 8696-8705). The present study tested whether diacylglycerol could mediate the insulin-induced and exercise-induced increases in glucose uptake by rat skeletal muscle in vivo. Glucose uptake by calf muscles of the rat was assessed by measuring cellular 2-deoxyglucose uptake in vivo. Diacylglycerol and ceramides in muscles frozen in situ were assayed with diacylglycerol kinase. Intravenous injection of 0.1 unit of insulin/rat resulted in a 6-fold increase in muscle 2-deoxyglucose uptake during the subsequent 25-min period. In contrast, no statistically significant changes in muscle diacylglycerol or ceramide levels were observed at 2, 5, 10, and 25 min after insulin injection. When calf muscles of the hindlimb were exercised in vivo for 25 min by electrical stimulation inducing one contraction/s, 2-deoxyglucose uptake by muscles was increased 15-fold. However, no statistically significant changes in muscle diacylglycerol or ceramide content were observed at 5, 10, 15, and 25 min of exercise. Although the findings do not exclude the possibility of a compartmentalized increase in diacylglycerol level, the present data suggest that diacylglycerol is not a mediator of the insulin-induced or exercise-induced augmentation of glucose uptake by skeletal muscle in vivo. Since interruption of nerve supply to the muscles makes the muscles insulin resistant (Turinsky, J., (1987) Am. J. Physiol. 252, R531-R537), the effect of denervation on diacylglycerol and ceramide levels in calf muscles of the rat was also examined. The denervation resulted in 21, 51, and 117% increases in muscle diacylglycerol levels at 3, 16, and 32 days after denervation, respectively. No statistically significant changes in muscle ceramide levels were observed at any postdenervation interval. Finally, the measured lipids were studied in muscles and livers of rats infused with supraphysiological doses of vasopressin (86 pmol/min). In controls, diacylglycerol concentrations of the muscles and liver did not significantly differ, but the liver exhibited a 5-fold higher level of ceramides than the muscles. Infusion of vasopressin for 5 min did not have a statistically significant effect on diacylglycerol concentration of the liver but continuation of the same infusion for 10 min resulted in a 63% increase in liver diacylglycerol. The 10-min infusion had no effect on muscle diacylglycerol concentration or ceramide levels in any of the tissues studied.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:1,2-Diacylglycerol and ceramide levels in rat skeletal muscle and liver in vivo. Studies with insulin, exercise, muscle denervation, and vasopressin. 218 32

The putative roles for the second messenger, diacylglycerol, were investigated in intact platelets using a novel diacylglycerol kinase inhibitor, R 59 949, or (3-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-2,3- dihydro-2-thioxo-4(1H)-quinazolinone). The compound inhibited the diacylglycerol kinase in a concentration-dependent manner (10(-8) to 10(-5) M) in isolated platelet membranes and in intact platelets. When platelets were stimulated with vasopressin in the presence of the compound, protein kinase C activity was markedly increased; the formation of inositol phosphates, the increase in intracellular Ca2+ and shape-change reaction were antagonized while the vasopressin-induced polyphosphoinositide synthesis was amplified, and this in a distinct inositolphospholipid pool. In the presence of R 59 949, vasopressin- as well as collagen-induced release reaction and aggregation was strongly increased, independently of the formation of arachidonate metabolites. It is concluded that diacylglycerol formed after receptor activation, likely by activating the protein kinase C, plays an important role in the propagation of platelet functional responses in casu aggregation and secretion and controls the termination of the primary receptor coupled responses.
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PMID:The role of endogenously formed diacylglycerol in the propagation and termination of platelet activation. A biochemical and functional analysis using the novel diacylglycerol kinase inhibitor, R 59 949. 253 41

Plasma-membrane fractions were prepared from the livers of rats injected with 0.15 M-NaCl (controls) or vasopressin (1 nmol/kg body wt.). When assayed in the presence of deoxycholate, vasopressin increased the Vmax. of plasma-membrane diacylglycerol kinase 2-4-fold, and the apparent Km of the enzyme for 1,2-dioleoyl-sn-glycerol was doubled. The effect of vasopressin on the Vmax. of plasma-membrane diacylglycerol kinase was twice as great between pH 7 and 8.5 than at pH 6 or 6.5. Vasopressin doubled the activity of diacylglycerol kinase in the plasma-membrane fraction when the enzyme was assayed with phosphatidylserine rather than deoxycholate as stimulator, and when either 1-stearoyl-2-arachidonoyl-sn-glycerol or 1,2-dioleoyl-sn-glycerol was the substrate. In perfused livers vasopressin (10 nM) increased the Vmax. of plasma-membrane diacylglycerol kinase 2-fold, and phenylephrine (3 microM) gave a similar effect. Vasopressin doubled diacylglycerol kinase activity in hepatocytes that had been preincubated for 55 min, but not in cells that had only been preincubated for 15 min.
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PMID:Activation of rat liver plasma-membrane diacylglycerol kinase by vasopressin and phenylephrine. 285 Aug 2

Isolated rat hepatocytes responded to a variety of Ca2+-mobilizing agents (vasopressin, angiotensin II, epinephrine, epidermal growth factor, ATP, and ADP) with a rapid increase in phosphatidate mass, as measured by a sensitive new method. When hepatocytes were incubated with vasopressin (10(-8) M), phosphatidate levels increased 2-3-fold in 2 min, but there was no significant increase in diacylglycerol at this time. Changes in the fatty acid composition of phosphatidate also preceded those in diacylglycerol. De novo synthesis of phosphatidate from [3H]glycerol was unaffected by vasopressin in short-term incubation. Incubation of washed rat liver plasma membranes with GTP gamma S caused a time-dependent increase in phosphatidate. When membranes were incubated with GTP gamma S and [gamma-32P]ATP, no incorporation of 32P into phosphatidate was observed. This excludes the phospholipase C-diacylglycerol kinase pathway and suggests that a phospholipase D activity produced the phosphatidate. At submaximal concentrations of GTP gamma S, ATP and ADP stimulated membrane phosphatidate formation, presumably by acting through P2-purinergic receptors. Only phosphatidylcholine, among the major phospholipids, decreased in the membranes in response to GTP gamma S. The fatty acid composition of the phosphatidate produced in response to vasopressin in hepatocytes also suggests that phosphatidylcholine may be the source of hormonally elicited phosphatidate. We conclude that Ca2+-mobilizing hormones mainly increase phosphatidate levels in hepatocytes by a mechanism that does not involve phosphorylation of diacylglycerol or de novo synthesis but involves a guanine nucleotide-binding protein coupled to phospholipase D.
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PMID:Phosphatidate accumulation in hormone-treated hepatocytes via a phospholipase D mechanism. 311 99

In hepatocytes pre-labelled with [3H]glycerol, compound R59022 (6-[2-(4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl)ethyl]-7- methyl-5H-thiazolo[3,2-alpha]pyrimidin-5-one) and 2-bromooctanoate each increased the amount of radioactivity in diacylglycerols. R59022 mimicked the actions of 12-O-tetradecanoylphorbol 13-acetate in completely abolishing the activation by adrenaline (but not that by vasopressin or glucagon) of glycogen phosphorylase a, and in decreasing the activity of glycogen synthetase. Exogenous dioctanoylglycerol caused a small inhibition of adrenaline-stimulated phosphorylase activity. The concentration of R59022 which gave half-maximal inhibition of adrenaline-stimulated phosphorylase activity was 15 microM. Maximal inhibition was observed within 2 min of addition of R59022. 2-Bromooctanoate activated phosphorylase by a process independent of changes in cyclic AMP and Ca2+, and decreased glycogen synthetase. It is concluded that in hepatocytes (i) diacylglycerols which accumulate as a result of the inhibition of diacylglycerol kinase by R59022 activate protein kinase C and (ii) 2-bromooctanoate increases diacylglycerols but also has other effects on hepatocyte metabolism.
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PMID:Effects of inhibitors of diacylglycerol metabolism on protein kinase C-mediated responses in hepatocytes. 313 Aug 94

Activators of protein kinase C, a calcium- and phospholipid-dependent protein kinase, inhibit vasopressin-stimulated water flow in toad bladder. To determine the biochemical mechanisms of this inhibition, we examined the effects of activators of protein kinase C on arginine vasopressin (AVP)-stimulated adenylate cyclase activity in cultured rabbit cortical collecting tubular cells. The phorbol ester, 4 beta-phorbol 12-myristate 13-acetate (PMA), the diacylglycerol, 1-oleyl-2-acetyl glycerol (OAG), and the diacylglycerol kinase inhibitor, R59022, all rapidly activate protein kinase C in collecting tubular cells. Pretreatment with PMA produces a delayed inhibition (greater than or equal to 4 h) of AVP-stimulated adenylate cyclase activity. The 4-h time lag suggests that the effects of protein kinase C are mediated indirectly, possibly as a consequence of stimulating cell proliferation. PMA does not inhibit cholera toxin- or forskolin-stimulated adenylate cyclase activity, suggesting an effect on the vasopressin receptor or coupling of the receptor to the stimulatory guanine nucleotide regulatory protein. Neither prostaglandins nor the inhibitory guanine nucleotide regulatory protein appear to mediate this effect. In contrast, treatment with either OAG or R59022 produces a rapid inhibition of both AVP- and forskolin-stimulated adenylate cyclase activity suggesting a prominent distal site of action, presumably at the catalytic subunit of adenylate cyclase. The results demonstrate that different activators of protein kinase C inhibit AVP-stimulated adenylate cyclase activity by distinctly different mechanisms possibly by altering the substrate specificity or activating multiple forms of the kinase. These results have important implications when using different activators to study the biological effects of protein kinase C.
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PMID:Phorbol esters inhibit adenylate cyclase activity in cultured collecting tubular cells. 333 16

The present work aimed to determine the role played by protein kinase-C (PKC) in the alpha 1-adrenoceptor-induced activation of hepatic metabolism. The following observations indicate that activation of PKC is a condition necessary for alpha 1-adrenoceptor activation of hepatic functions, but not sufficient to mimic the receptor-mediated effects in the absence of external physiological stimuli. 1) alpha 1-Adrenoceptor activation promoted the translocation of PKC from the cytosol to its active form in the plasma membrane. 2) Activation of PKC by the phorbol ester 12-myristate 13-acetate or exogenous diacylglycerols or by elevation of endogenous levels of diacylglycerols by inhibiting diacylglycerol kinase mimicked the alpha 1-adrenoceptor-mediated actions. However, the time course and magnitude of the nonreceptor responses differ from those mediated by alpha 1-adrenoceptor activation. In addition, nonreceptor-mediated activation of PKC decreased the alpha 1-adrenoceptor responsiveness. 3) Inhibition of PKC by either H-7 [1-(5-isoquinolinilsulfonyl)2-methylpiperazine] or staurosporine inhibited all of the alpha 1-adrenoceptor-induced responses, except gluconeogenesis. The vasopressin effects were not inhibited by H-7, indicating that PKC activation is a distinct feature of the hepatic alpha 1-adrenoceptor activation that is not shared by all the Ca(2+)-mobilizing agonists. The diacylglycerol-PKC branch of the alpha 1-adrenoceptor signaling pathway seems to control the sustained phase of stimulation of hepatic functions. In these studies we have also observed that phorbol 12-myristate 13-acetate produces a concentration-dependent inhibition of hepatic respiration. However, decreased energy availability does not seem to be the cause of its action to decrease alpha 1-adrenoceptor responsiveness.
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PMID:Role of protein kinase-C in the alpha 1-adrenoceptor-mediated responses of perfused rat liver. 840 60

The effect of phospholipid and MgATPase modulation was evaluated on the cardiovascular actions of vasopressin in normal and lithium carbonate- (Li2CO3) induced polyuric rats. We examined the effects of the phospholipase inhibitor neomycin, the diacylglycerol kinase II inhibitor R59949 and the MgATPase activator sphingosine on heart rate (HR) and blood pressure (BP) responses to vasopressin analogues lysine vasopressin (LVP) and arginine vasopressin (AVP). R59949 (20 microg/kg) produced an increase while sphingosine (30 microg/kg) caused a decrease in HR responses in both control and polyuric rats. Pretreatment with sphingosine caused significant enhancement of LVP- (10 microg/kg) induced bradycardia in polyuria rats compared with control animals (p < 0.01). R59949 induced a potentiation of vasopressin-induced bradycardia in control animals compared with polyuria rats. Pretreatment with sphingosine and R59949 produced a significant increase in BP per se and potentiated the actions of LVP in control animals, while the response in the lithium-treated animals was attenuated. Neomycin caused a reduction in HR and BP in control and lithium-treated animals. To evaluate the central role of the MgATPase enzyme we used sphingosine, which significantly increased the locomotor activity of lithium-treated animals, suggesting a possible central interaction of lithium and MgATPase (p < 0.05). These results strongly suggest that phospholipid mediators and MgATPase modulation contribute to the alteration of the cardiovascular effects of vasopressin in lithium carbonate-induced polyuric rats.
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PMID:Phospholipid mediators and MgATPase modulation causes changes in the cardiovascular effects of vasopressin in lithium carbonate-induced polyuric rats. 1531 3


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