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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic GMP-dependent protein kinase displays an uneven distribution in brain, being highly concentrated only in cerebellar Purkinje cells. Using DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32,000) as exogenous substrate, and performing assays in the absence or presence of the protein inhibitor of cyclic AMP-dependent protein kinase, we have now identified both cyclic AMP-dependent and cyclic GMP-dependent protein kinase activities in the rat neostriatum and substantia nigra. Quinolinic acid-induced degeneration of neostriatal neurons and the straitonigral fibers emanating from neostriatal neurons decreased the activities of both cyclic nucleotide-dependent enzymes by 70-85% in the neostriatum, while cyclic GMP-dependent protein kinase was decreased by 44% and cyclic AMP-dependent protein kinase was decreased by 18% in the substantia nigra. In the basal ganglia, cyclic GMP-dependent protein kinase therefore appears enriched in striatonigral neurons, while cyclic AMP-dependent protein kinase is present both in striatonigral neurons and in other cells. The results indicate that cyclic GMP-regulated protein phosphorylation may play a role in the function of distinct basal ganglion neurons.
J Mol Neurosci 1989
PMID:Localization of cyclic GMP-dependent protein kinase in rat basal ganglia neurons. 256 56

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by the cAMP as well as the calcium and cGMP second messenger systems. Treatment of intact rat PC12 cells with neuropeptides including secretin and vasoactive intestinal polypeptide (VIP) stimulated tyrosine hydroxylase activity 2 to 3-fold in vitro. Secretin (EC50 = 10 nM) was about 3 orders of magnitude more potent than VIP (EC50 = 3 microM). A combination of several protease inhibitors failed to enhance the potency of either peptide. Other members of the secretin family including glucagon and peptide histidine isoleucine (PHI) stimulated tyrosine hydroxylase activity to a lesser extent. Somatostatin, which is not homologous to secretin, was ineffective. The maximal response of tyrosine hydroxylase activation to 1 microM secretin occurred within 6-15 sec. Secretin, VIP, and forskolin also enhanced tyrosine hydroxylase activity (3,4-dihydroxyphenylalanine production) in intact cells, as determined by high performance liquid chromatography and electrochemical detection. Secretin, VIP, PHI, and glucagon increased the levels of cAMP in PC12 cells more than 10-fold, as determined by radioimmunoassay. We also demonstrated that cAMP is released from the cells into the incubation medium following secretin treatment. Secretin and VIP treatment also enhanced the activity of cAMP-dependent protein kinase in a concentration-dependent fashion, as measured subsequently in vitro. Based on the greater potency of secretin in comparison with VIP, PHI, and glucagon, we suggest that the PC12 cells contain a secretin-preferring receptor that increases cAMP levels and brings about an activation of tyrosine hydroxylase activity through the stimulation of cAMP-dependent protein kinase.
Mol Pharmacol 1989 Dec
PMID:Regulation of tyrosine hydroxylase activity in rat PC12 cells by neuropeptides of the secretin family. 257 21

Responsiveness to catecholamines may be blunted after prolonged exposure to an agonist; this phenomenon, termed desensitization, is often mediated by receptor down-regulation. beta-Adrenergic receptors mediate relaxation of vascular smooth muscle. We have examined the possibility that this response may be desensitized after prolonged exposure to increased concentrations of epinephrine. Rats were treated with epinephrine infusions (300 micrograms/kg/hr from a minipump) for 7 days and had levels of plasma epinephrine 70-fold greater than those of controls. The mesenteric artery rings from the epinephrine-treated rats contracted normally when exposed to serotonin; however, the extent of relaxation promoted by the beta-adrenergic agonist isoproterenol was blunted (86 +/- 4 vs. 43 +/- 9%; p less than 0.05). Acetylcholine and nitroglycerine, which may act through a cyclic GMP mechanism, caused virtually identical relaxation responses in both control and epinephrine-treated groups. To determine the mechanism for the loss in responsiveness to isoproterenol, we measured adrenergic receptors in individual mesenteric arteries using [125I]cyanopindolol. Specific binding of [125I]cyanopindolol was found to have the expected characteristics of interaction with beta receptors. There was no difference in the number of beta-adrenergic receptors between control and epinephrine-treated animals (24 +/- 5 vs. 26 +/- 6 fmol/mg of protein), although there was significantly marked down-regulation of beta-adrenergic receptors in hearts (23 +/- 2 vs. 10 +/- 1 fmol/mg of protein; p less than 0.001) and lungs (172 +/- 29 vs. 76 +/- 7 fmol/mg of protein; p less than 0.01) in the same rats. The ability of isoproterenol to stimulate cyclic AMP production in the mesenteric arteries from the two groups was not significantly different (20.3 +/- 3.5 vs. 23.8 +/- 4.7 pmol of cAMP/mg of protein/2 min). Furthermore, mesenteric artery relaxation was found to be decreased in response to the cyclic AMP analogue dibutyryl cyclic AMP (45 +/- 2.0 vs. 28 +/- 2.0%; p less than 0.001) in the epinephrine-infused rats. These data suggest that the desensitization of beta-adrenergic receptor-mediated smooth muscle relaxation may be caused by a mechanism distal to cyclic AMP production.
Mol Pharmacol 1985 Feb
PMID:Desensitization of beta-adrenergic receptor-mediated vascular smooth muscle relaxation. 257 3

The regulation of the biosynthesis of choriogonadotropin (hCG) in tissue culture by human first trimester placenta in the presence of the following cyclic nucleotides and 3-isobutyl-1-methylxanthine (IBMX) was studied (concentrations in parentheses): IBMX (0.1 mM), cAMP (1 mM) + IBMX (0.1 mM), cGMP (0.1 mM) + IBMX (0.1 mM), 8-bromo-cAMP (0.5 mM) and 8-bromo-cGMP (0.5 mM). The medium concentration of hCG follows an optimum curve at all conditions, showing highest values at day 3 of the culture. The efficacy of the substances to cause an increase in the hCG medium concentration was in the following order: IBMX less than control less than 8-bromo-cGMP = 8-bromo-cAMP less than cGMP + IBMX less than cAMP + IBMX. The synthesized hCG was examined with respect to its receptor binding activity (LH/hCG receptor of rat testes), the activities to stimulate adenylate cyclase as well as testosterone biosynthesis in purified mouse Leydig cells, the immunological activity, and the microheterogeneity in isoelectric focusing. Only in the presence of 8-bromo-cAMP, 8-bromo-cGMP, and cGMP + IBMX was hCG synthesized, which differs significantly in the investigated properties from hCG of the control cultures. Only in the presence of 8-bromo-cGMP is the ratio of receptor binding activity/immunological activity optimal (near 1). In the presence of both 8-bromo-cAMP and 8-bromo-cGMP, microheterogeneity of hCG in isoelectric focusing was diminished and the synthesis of more acidic hCG subpopulations was favoured.
Mol Cell Endocrinol 1985 Feb
PMID:Influence of cyclic nucleotides on receptor binding, immunological activity, and microheterogeneity of human choriogonadotropin synthesized in placental tissue culture. 257 62

Synthetic analogues of bacterial lipoprotein induce proliferation of murine small resting B lymphocytes. We investigated the role of proteinkinase C (PKC) activation in lipopeptide-induced B cell stimulation. Using a standardized extraction procedure, there was no change in membrane bound and soluble PKC activity upon stimulation with lipopeptide. However, omitting Ca2+ chelators from the standard extraction medium resulted in a decrease of membrane bound PKC activity after stimulation. Lipopeptide failed to induce phosphoinositide degradation and the generation of the two second messengers cAMP and cGMP. To test whether guanosinetriphosphate-binding proteins are involved in lipopeptide-induced signal transfer we investigated the effect of LiCl, choleratoxin and pertussistoxin on B lymphocyte proliferation. LiCl and pertussistoxin did not inhibit cell activation, whereas choleratoxin reduced the proliferation rate at concentrations higher than 0.5 micrograms/ml. Similar results were observed when LPS was used as mitogen, whereas the anti-immunoglobulin-induced B cell activation was inhibited by all three compounds. Our results show, that B cell activation by bacterial lipopeptides bypasses phosphatidylinositol metabolism and PKC translocation.
Mol Immunol 1989 Sep
PMID:B cell activation by synthetic lipopeptide analogues of bacterial lipoprotein bypassing phosphatidylinositol metabolism and proteinkinase C translocation. 260 27

The binding of the cyclic adenosine 3',5' monophosphate receptor protein (CRP or CAP) of Escherichia coli to non-specific DNA and to a specific lac recognition sequence has been investigated by circular dichroism (c.d.) spectroscopy. The effect of cAMP and cGMP on the co-operative non-specific binding was also studied. For the non-specific binding in the absence of cAMP a c.d. change (decrease of the intensity of the positive band with a shift of its maximum to longer wavelength) indicates that the DNA undergoes a conformational change upon CRP binding. This change might reflect the formation of the solenoidal coil previously observed by electron microscopy. The amplitude of the c.d. change increases linearly with the degree of saturation of the DNA and does not depend on the size of the clusters of CRP bound. From the variation of the c.d. effect as a function of the ionic strength, the product K omega (K, the intrinsic binding constant and omega, the co-operativity parameter) could be determined. The number of ion pairs involved in complex formation between CRP and DNA was found to be six to seven. Experiments performed with several DNAs, including the alternating polymers poly[d(A-T)] and poly[d(G-C)], demonstrated that the conformational change does not depend on the DNA sequence. However, in the presence of cAMP the c.d. spectrum of the DNA shows only a small variation upon binding CRP. In contrast, in the presence of cGMP the conformational change of the DNA is similar to that observed when non-liganded CRP binds. For the specific lac operon binding, the c.d. change is different from those observed for non-specific binding in the presence or absence of cAMP. These results emphasize the high variability of the DNA structure upon binding the same protein.
J Mol Biol 1987 May 05
PMID:Interaction between the cyclic AMP receptor protein and DNA. Conformational studies. 282 Dec 69

The influence of cAMP on the cell-to-cell diffusion of Lucifer Yellow CH in heart muscle was further investigated. It was found that isoproterenol (10(-5) M) enhanced the diffusion coefficient (D) from 4 +/- 0.63 X 10(-7) cm2/s (control) to 2.4 +/- 0.66 X 10(-6) cm2/s. Dibutyryl-cAMP (5 X 10(-4) M) plus theophylline (0.4 mM) also increased the cell-to-cell diffusion of Lucifer Yellow CH (D = 3.2 +/- 0.69 X 10(-6) cm2/s). The effect of dBcAMP was increased by theophylline. Since the permeability of the surface cell membrane to the dye is negligible in presence of these drugs and the binding of Lucifer Yellow CH to cytoplasmic proteins was not altered, it is thus concluded that the enhanced longitudinal diffusion of the dye was due to an increase in junctional permeability. As the enhanced cell-to-cell diffusion of the dye caused by isoproterenol was quickly reversed the hypothesis of a greater synthesis of intercellular channels seems unlikely. Acetylcholine (10(-5) M) that increases the intercellular concentration of cGMP had no effect on cell-to-cell diffusion of the dye. The present results support the view that cAMP is a modulator of junctional permeability in heart muscle.
J Mol Cell Cardiol 1987 Aug
PMID:Further studies on the influence of cyclic nucleotides on junctional permeability in heart. 282 96

Based on the pharmacophoric relationship heterocycle-phenyl-imidazole (H-P-I) and upon consideration of several potent inhibitors of cardiac cAMP phosphodiesterase, a topographical model of this receptor is proposed. The model consists of two binding sites which interact with H, two steric features, preferential rotation of P away from coplanarity with H, and a binding site for an electron-rich system (I). It is supported by molecular modeling studies and accommodates a variety of inhibitors. It also encompasses the active site of the enzyme and can distinguish cAMP from cGMP as substrates.
Mol Pharmacol 1988 Jan
PMID:Cardiotonic agents. 3. A topographical model of the cardiac cAMP phosphodiesterase receptor. 282 95

Canine and guinea-pig left ventricular muscle contains multiple molecular forms of phosphodiesterase (PDE) which vary according to substrate specificity, stimulation by calmodulin and response to various selective and nonselective phosphodiesterase inhibitors. Both species possess a cyclic AMP-specific form of phosphodiesterase (PDE III). In the dog, both soluble and particulate forms of PDE III are present. The particulate form of PDE III is potently inhibited by cyclic GMP and the selective PDE III inhibitors imazodan (CI-914) and cilostamide, but is only weakly inhibited by the selective PDE III inhibitors Ro 20-1724 and rolipram. In contrast, the soluble form of PDE III in canine left ventricle is only weakly inhibited by cyclic GMP, imazodan and cilostamide, but is potently inhibited by Ro 20-1724 and rolipram. Guinea-pig left ventricle contains only one subclass of PDE III, which is potently inhibited by cyclic GMP, imazodan and cilostamide, but not by Ro 20-1724 or rolipram. However, whereas the imazodan-sensitive subclass of PDE III is a particulate enzyme in the canine left ventricle, in the guinea-pig this subclass of PDE III is a soluble enzyme. Both soluble and particulate PDE III's are (i) insensitive to calmodulin; (ii) possess comparable Km and Vmax values for hydrolysis of cyclic AMP; (iii) are equally inhibited by the nonselective PDE inhibitor theophylline, and (iv) are eluted from DEAE-cellulose anion-exchange resin by comparable concentrations of sodium acetate. The demonstration of distinct subclasses of the cyclic AMP-specific phosphodiesterase (PDE III) in canine left ventricular muscle associated with different domains of the cell suggests compartmentation of cyclic AMP. In addition, the observation that the imazodan-sensitive form of PDE III is a particulate enzyme in canine left ventricle and a soluble enzyme in guinea-pig left ventricle may explain the species differences which exist regarding the positive inotropic response to imazodan in these two species.
J Mol Cell Cardiol 1987 Oct
PMID:Subclasses of cyclic AMP phosphodiesterase in cardiac muscle. 283 Apr 2

The objective of this study was to investigate the effects of 4 beta-phorbol 12-myristate 13-acetate (4 beta-PMA)--a potent activator of protein kinase C--on the responsiveness of mouse Leydig cells to stimulation with rat atriopeptin II (rAP-II). We report that, in these cells, the stimulation of testosterone production by rAP-II could be inhibited in a dose-dependent manner by 4 beta-PMA (1-200 nM). In contrast, the basal steroidogenesis was stimulated 2-fold by 4 beta-PMA. There was no inhibition of testosterone production when the cells were stimulated with 8-bromo cyclic GMP (8Br-cGMP) in the presence of 4 beta-PMA. Furthermore, addition of 4 beta-PMA resulted in a marked reduction in the amount of cGMP accumulated in response to rAP-II stimulation. 4 alpha-Phorbol 12-myristate 13-acetate (4 alpha-PMA) was found to have no effect at all. The inhibitory effect of 4 beta-PMA on steroidogenesis could be completely reversed by the addition of 0.25 mM 3-isobutyl 1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Also, the 4 beta-PMA-induced lowering of cGMP content could be partially reversed by IBMX. Membrane fractions from cells treated with 4 beta-PMA or 4 alpha-PMA did not differ in their contents of either basal or rAP-II-stimulated guanylate cyclase activities. We conclude that the 4 beta-PMA-mediated inhibition of testosterone production by Leydig cells stimulated with rAP-II results from an activation of a phosphodiesterase enzyme, hypothetically through an activated protein kinase C. This leads to a reduction in the cellular cGMP content through an increased metabolic removal of cGMP formed in response to rAP-II stimulation.
Mol Cell Endocrinol 1988 Mar
PMID:Effect of a tumour-promoting phorbol ester on atrial peptide-induced testosterone production and cyclic GMP accumulation by isolated mouse Leydig cells. 283 43


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