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)

The contribution of hormone-stimulated glycogenolysis to hepatic glucose production was studied in hepatocytes from streptozotocin diabetic rats. To this end, the activation of glycogen phosphorylase by glucagon, vasopressin, and the alpha 1-adrenergic agonist phenylephrine was compared in hepatocytes from normal and diabetic rats and related to glycogen content, glucose production, and microsomal glucose-6-phosphatase activity. Streptozotocin-induced diabetes reduced the glycogen content and the amount of total (a + b) phosphorylase in hepatocytes proportionally to the severity of the disease. In cells from severely diabetic rats (group 1), the responsiveness of activation of phosphorylase to the hormones was reduced by about half, consistent with a 45% reduction in total phosphorylase. In addition, the sensitivity of phosphorylase activation to all hormones investigated was decreased by about 1 order of magnitude or more in cells of this group. In hepatocytes from rats with milder diabetes (group 2), maximal phosphorylase activation reached an intermediate value between that of the control group and of group 1. In response to all hormones investigated, group 2 diabetic rat hepatocytes produced less glucose than control rat liver cells, while in group 1 there was no increase in glucose production at all, presumably because glycogen concentration was too low. However, in group 2 diabetic rat hepatocytes, glucagon-stimulated glucose production, unlike phosphorylase activation, did not show decrease sensitivity, presumably because glucose-6-phosphatase activity is increased by diabetes. Our results thus indicate that hormone-stimulated liver glycogenolysis is unlikely to contribute to enhanced glucose production in insulin-deficient diabetes, despite increased glucose-6-phosphatase activity.
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PMID:Hormone-stimulated glucose production from glycogen in hepatocytes from streptozotocin diabetic rats. 165 43

Swelling of hepatocytes increases the concentration of inositol 1,4,5-trisphosphate, Ca2+ and cAMP, without activating glycogen phosphorylase. In these hepatocytes, the activation of phosphorylase by suboptimal concentrations of vasopressin or angiotensin II was partly antagonized.
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PMID:Hepatocyte swelling increases inositol 1,4,5-trisphosphate, calcium and cyclic AMP concentration but antagonizes phosphorylase activation by Ca2(+)-dependent hormones. 184 8

The mechanisms through which Ca2+ mobilization in rat hepatocytes results in the loss of total activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase [Zammit & Caldwell (1990) Biochem. J. 269, 373-379] were investigated. The loss of total activity was shown to be paralleled by an equal loss of immunoreactive HMG-CoA reductase protein after exposure of hepatocytes to optimal concentrations of vasopressin plus glucagon for 40 min. This loss of enzyme protein was due to an inhibition of enzyme synthesis; the rate of degradation was unaffected. Other Ca(2+)-mobilizing conditions (phenylephrine, glucagon, vasopressin added singly and A23187) also resulted in graded inhibition of synthesis of HMG-CoA reductase. These effects were accentuated by omission of Ca2+ from the cell incubation medium, suggesting that it is the depletion of an intracellular InsP3-sensitive pool of Ca2+ to which synthesis of HMG-CoA reductase is sensitive. In agreement with this we found that t-butylhydroxybenzoquinone, which inhibits the activity of the Ca(2+)-ATPase of the endoplasmic-reticular membrane, mimicked the action of Ca(2+)-mobilizing hormones. However, taurolithocholate, which transiently mobilizes Ca2+ from the same pool, was ineffective. All these effects on HMG-CoA reductase were accompanied by parallel inhibition of 35S incorporation from [35S]methionine into total protein, suggesting that inhibition of reductase synthesis formed part of a generalized response of the hepatocyte to Ca2+ mobilization. Inhibition of the rate of synthesis of HMG-CoA reductase was, however, more responsive to Ca2+ mobilization in the absence of added Ca2+ from the extracellular medium. The concentrations of vasopressin required to elicit the inhibition of synthesis of HMG-CoA reductase were of the same order as those that elicited activation of glycogen phosphorylase in hepatocytes.
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PMID:Rapid decrease in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase protein owing to inhibition of its rate of synthesis after Ca2+ mobilization in rat hepatocytes. Inability of taurolithocholate to mimic the effect. 195 35

PRL at a physiological concentration (10(-8) M) produced a very rapid and transient increase in 45Ca efflux in freshly isolated hepatocytes, which reached the highest value within 5 min and returned to baseline level after 20 min. PRL-induced 45Ca2+ efflux resulted in a loss of 15% of total cell calcium, which was similar to that found in vasopressin-treated cells. However, in contrast with the PRL effect, 45Ca2+ efflux induced by vasopressin was sustained. We demonstrate by using two different approaches, glycogen phosphorylase-a activation and direct cytosolic calcium concentration [( Ca2+]i) measurements, that PRL elicits a [Ca2+]i increase. The treatment of hepatic cells with PRL caused a 4-fold stimulation in glycogen phosphorylase-alpha activity after 2 min of PRL addition. Direct [Ca2+]i determination in fluo-3-loaded hepatocytes showed a 11% increase after 5 min of PRL addition. Similar data were observed in hepatocytes stimulated either with vasopressin (10(-7) M) or calcium ionophore A23187 (200 nM). The increase in [Ca2+]i promoted by PRL was independent of extracellular calcium or voltage-operated calcium channels. The data demonstrate that calcium is involved in the intracellular signaling of PRL in liver cells and that PRL initiates its action by a Ca2+ mobilization from the intracellular stores.
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PMID:Prolactin increases cytosolic free calcium concentration in hepatocytes of lactating rats. 195 71

The [Arg8]vasopressin (AVP) receptor expressed by human hepatocytes was characterized, and compared with the rat hepatic V1a vasopressin receptor subtype. In addition to determining the pharmacological profile of the human receptor, the cellular responses to AVP were measured in human and rat hepatocytes by assaying glycogen phosphorylase alpha activity and DNA synthesis. Marked differences were observed between human and rat hepatocytes regarding vasopressin receptors and the intracellular consequences of stimulation by AVP. Data presented in this paper demonstrate the following, (i) Vasopressin V1a receptors are present in low abundance on human hepatocytes. (ii) Species differences exist between human and rat V1a receptors with respect to the affinity of some selective antagonists. (iii) AVP-stimulated glycogen phosphorylase a activation in human hepatocytes was approx. 5% of that observed in rat cells. (iv) In contrast with rat hepatocytes, DNA synthesis in human cells in culture was not stimulated by AVP. It is concluded that vasopressin plays only a minor role in the regulation of human hepatic function. Furthermore, conclusions drawn from observations made with AVP and its analogues on rat hepatic function cannot be directly extrapolated to the human situation.
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PMID:Characterization of the human liver vasopressin receptor. Profound differences between human and rat vasopressin-receptor-mediated responses suggest only a minor role for vasopressin in regulating human hepatic function. 203 69

The hormonal control of glycogen synthase and phosphorylase interconversion was investigated in hepatocytes isolated from lean and genetically obese (fa/fa) rats. In cells from obese animals, the inactivation of synthase by 4 beta-phorbol 12 beta-myristate 13 alpha-acetate (PMA), phospholipase C, vasopressin and the alpha 1-adrenergic agonist phenylephrine was markedly impaired, and the property of PMA to counteract phosphorylase activation by phenylephrine was attenuated. The maximal response of phosphorylase activation to phenylephrine and vasopressin was increased in obese-rat hepatocytes, but the sensitivity to these hormones was similar to that in lean-rat hepatocytes. These observations indicate that the defect in protein kinase C that we reported previously in heart of insulin-resistant fa/fa rats [van de Werve, Zaninetti, Lang, Vallotton & Jeanrenaud (1987) Diabetes 36, 310-319] is probably also expressed in liver.
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PMID:Altered regulation of glycogen metabolism by vasopressin and phenylephrine in hepatocytes from insulin-resistant obese (fa/fa) rats. Role of protein kinase C. 211 21

The ability of Ca2(+)-mobilizing hormones to promote changes in the subcellular distribution of protein kinase C (PKC) was studied in isolated hepatocytes. In recently isolated cells the distribution of PKC between the soluble and particulate fractions was 47 and 53% respectively. Exposure of the hepatocytes to 100 nM-vasopressin produced an increased phosphoinositide turnover, as reflected by the changes in the concentrations of inositol trisphosphate and Ca2+, and in glycogen phosphorylase a activity. However, the distribution of both PKC activity and [3H]phorbol dibutyrate binding between the cytosol and the membranes remained unchanged under these conditions. To determine the threshold values of the concentrations of Ca2+ and diacylglycerol required to produce a redistribution of PKC, the hepatocytes were treated with the Ca2+ ionophore ionomycin, and with permeant diacylglycerol derivatives. Hepatocytes incubated in the presence of 100 nM-vasopressin required concentrations of Ca2+ 2.5 times those produced physiologically by the hormone to produce translocation of PKC from the cytosol to the membranes. These studies suggest that, at least in hepatocytes, activation of PKC in response to Ca2(+)-mobilizing hormones involves only the pre-existent membrane-bound enzyme without affecting the soluble enzyme.
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PMID:Lack of translocation of protein kinase C from the cytosol to the membranes in vasopressin-stimulated hepatocytes. 216 91

We investigated the effects of conditions that induce Ca2+ mobilization from intracellular stores and Ca2+ influx into hepatocytes on the expressed and total (fully dephosphorylated) activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Vasopressin and phenylephrine when added alone had small or negligible effects on the phosphorylation state of the enzyme, as judged from the expressed/total activity ratio. However, when added in combination with glucagon, they elicited appreciable increases in the phosphorylation of the enzyme. Glucagon on its own had no effect either on phosphorylation state or on total HMG-CoA reductase activity during 40 min of incubation. Under conditions of sustained Ca2+ influx (i.e. vasopressin or phenylephrine plus glucagon), there was a marked loss of total HMG-CoA reductase activity. This effect was more pronounced when vasopressin was used; 50% of the enzyme activity was lost within 40 min. The involvement of Ca2+ in these effects was verified directly by the use of ionophore A23187. Its addition to hepatocytes resulted both in a very pronounced increase in the phosphorylation state of the enzyme and in the loss of 50% of the total activity within 30 min. There was no correlation between the ability of any set of conditions to increase the phosphorylation of the enzyme and the subsequent loss of total HMG-CoA reductase activity. The latter parameter appeared to be directly related, however, to the maintenance of prolonged Ca2+ influx, as indicated by the continued activation of glycogen phosphorylase, measured in the same cells. The lack of a causal relationship between increased phosphorylation and loss of total activity was demonstrated directly by studies in which okadaic acid was used to induce phosphorylation of HMG-CoA reductase in hepatocytes by inhibition of phosphatase 1 and 2A activities. This was not accompanied by any loss of total enzyme activity. Neither did okadaic acid enhance the loss of reductase induced by A23187 when the two agents were added together. It is concluded that altered Ca2+ fluxes in hepatocytes in vivo, under conditions of acute or chronic stress (such as may be associated with trauma or diabetes respectively), may be involved in the regulation of the expression of HMG-CoA reductase activity through alteration of enzyme concentration in the liver.
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PMID:Conditions that result in the mobilization and influx of Ca2+ into rat hepatocytes induce the rapid loss of 3-hydroxy-3-methylglutaryl-CoA reductase activity that is not reversed by phosphatase treatment. 216 66

The prominent protein phosphatases involved in liver glycogen metabolism are the AMD (ATP, Mg-dependent, type-1) and PCS (polycation-stimulated, type-2A) phosphatases. The glycogen synthase phosphatase activity, measured from the rate of activation of liver glycogen synthase, is virtually accounted for by AMD phosphatases; the bulk of the activity belongs to the glycogen-bound protein phosphatase G and a small part is present in the cytosol. The major part of the phosphorylase phosphatase activity present in the post-mitochondrial supernatant is shared by protein phosphatase G and cytosolic enzymes, and a minor part belongs to a microsomal AMD phosphatase. In the liver cytosol, the phosphorylase phosphatase activity is about equally distributed between AMD and PCS phosphatases. Studies in vivo as well as on isolated, perfused livers have shown that glucagon (which raises the level of cyclic AMP) as well as vasopressin (which increases the cytosolic Ca2+ concentration) decrease the phosphorylase phosphatase activity in liver extract or cytosol (filtered through Sephadex G-25) by about 25% within a few minutes. These effects were not additive, and the activity of glycogen synthase phosphatase was not affected. Conversely, insulin as well as glucose increased both phosphatase activities by about 25%, and these effects were additive. Vanadate mimicked the effect of insulin on the perfused liver. All the activity changes were only observed when the assays were performed at high tissue concentration. Upon subcellular fractionation all the effects were well expressed in the cytosol, but not in the particulate fraction (glycogen and microsomes). However, quantitatively the hormonal responses were largely lost during the fractionation procedure; they could be restored by recombination of the liver cytosol from a hormone-treated rat with the particulate fraction from either a treated or an untreated animal. It appears that the effects of glucagon, insulin and glucose are mediated by cytosolic, transferable effectors of the Vmax of protein phosphatases. These effectors are eluted in the void volume of a Sephadex G-25 column. Rats of the gsd/gsd strain, which have a genetic deficiency of hepatic phosphorylase kinase, responded to an injection of insulin plus glucose with a normal increase in the cytosolic phosphorylase phosphatase activity. In contrast, they failed to respond to glucagon as well as vasopressin. A transient 80% inhibition of the phosphorylase phosphatase activity could be induced in vitro in a concentrate liver cytosol from Wistar rats upon addition of MgATP.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Short-term hormonal control of protein phosphatases involved in hepatic glycogen metabolism. 216 98

To pursue our studies of the effects of adrenalectomy on the adrenergic regulation of phosphorylase a, cAMP, cell calcium, and Ca2+ signaling in rat hepatocytes (Studer, R.K., and Borle, A.B. (1984) Biochim. Biophys. Acta 804, 377-385; Freudenrich, C.C., and Borle, A.B. (1988) J. Biol. Chem. 263, 8604-8610), we have further examined the alpha 1-adrenergic pathway in adrenalectomized and sham-operated male rats. We measured the number and affinity of alpha 1-adrenergic receptors, the cytosolic free Ca2+ concentration [(Ca2+]i) of hepatocytes with aequorin, inositol triphosphate (IP3) accumulation, and Ca2+ influx and efflux across the plasma membrane. We also compared the effects of vasopressin with those obtained with epinephrine. We found that the number of alpha 1-adrenergic receptors was slightly depressed (-23%), but that their affinity was unchanged. However, IP3 accumulation evoked by epinephrine was decreased 50%. This is probably the main cause for the depressed peak rise in [Ca2+]i we previously observed and reported. We also found that the basal resting Ca2+ influx was increased after adrenalectomy. Experiments with the beta-blocker propranolol, which abolished the epinephrine-evoked increase in Ca2+ influx, suggest that this effect may be mediated by cAMP, at least in adrenalectomized animals. The effects of vasopressin on IP3 [Ca2+]i and Ca2+ influx and efflux were also significantly decreased after adrenalectomy, indicating that alpha 1-adrenergic-mediated and other IP3-dependent Ca2+ signaling pathways are depressed after adrenalectomy.
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PMID:Effect of adrenalectomy on Ca2+ signaling in rat hepatocytes. 217 39


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