Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The subcellular distribution of PI-PLC beta 1, gamma 1, and delta 1 has been investigated in rat liver by western blot and immunohistochemical analysis with a panel of isoform-specific antibodies. The data obtained in situ on cryo-sectioned tissue indicate that PI-PLC beta 1 is predominantly nuclear, while gamma 1 is largely cytoplasmic and delta 1 is sharply restricted to the cytoplasm. In fractionation experiments, the Western blot analysis indicated that the recovery of the nuclear isoforms beta 1 and gamma 1 was not affected by the removal of the nuclear membrane, and that the two enzymes persisted in nuclear matrix and lamina, obtained after nuclease digestion and extraction with high salt and detergent. The assay of the phosphodiesterase activity in different cell fractions correlates with the observed relative abundance of the enzymes, and specific inhibition with neutralizing anti-beta 1 and -gamma 1 isoforms confirms that these are the enzymes active at the nuclear level. These results demonstrate that in rat liver cells, as in other cell types, different members of the PI-PLC family show a discrete intracellular distribution, and suggest that PI-PLC beta 1 and gamma 1 play a central role in modulating the nuclear phosphoinositide cycle.
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PMID:Identification of PI-PLC beta 1, gamma 1, and delta 1 in rat liver: subcellular distribution and relationship to inositol lipid nuclear signalling. 851 96

In order to characterize the structure and regulation of members of the cAMP-specific phosphodiesterase (PDE) family (Type IV PDEs; PDE4 family), we have cloned from the rat a cDNA, pRPDE39, encoding a novel member of this family, which we call RNPDE4A8. Sequencing of the pRPDE39 cDNA shows it to be encoded by the rat PDE4A gene, but to differ from two other PDE4A transcripts, RD1 (pRPDE8; RNPDE4A1) and pRPDE6 (RNPDE4A5), by the presence of a unique region at its 5' end, consistent with alternative mRNA splicing. The pRPDE39 cDNA encodes a predicted protein of 763 amino acids, of which all but 21, located at the extreme amino terminus, are found in the pRPDE6 protein. Expression of pRPDE39 in COS cells produced a protein of 98 +/- 1.4 kDa, as determined by immunoblotting with an antiserum specific to the carboxyl-terminal regions of all PDE4A proteins, compared to a predicted value of 87.5 kDa. RNase protection analysis detected pRPDE39 mRNA only in testis. Immunoblotting of testis extracts demonstrated two bands of 97 +/- 2 and 87 +/- 3 kDa, the larger of which co-migrated with the band seen in COS cells expressing pRPDE39. COS cell expressed pRPDE39 partitioned between a high speed pellet (particulate) fraction (15% of protein; 8% of activity) and a cytosolic fraction. The particulate fraction had a Km for cAMP of 3.3 +/- 0.6 microM, and the cytosolic fraction a Km of 5.4 +/- 2.8 microM. The Vmax values for the pRPDE39 protein, relative to the RD1 protein, were 0.16 +/- 0.06 and 0.29 +/- 0.05 for the particulate and cytosolic forms, respectively. The pRPDE39-encoded PDE activity could not be removed from the particulate fraction by high salt concentrations, or by nonionic detergents. The pRPDE39-encoded enzyme was inhibited by rolipram at an IC50 of 0.5 +/- 0.2 microM for the particulate form and 1.0 +/- 0.2 microM for the cytosolic form, which are values typical of PDE4 family members. The highly tissue-specific distribution of the pRPDE39 mRNA suggest that the pRPDE39 protein functions to modulate a cAMP signaling pathway that is present largely, if not exclusively, in the testis.
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PMID:Alternative splicing of cAMP-specific phosphodiesterase mRNA transcripts. Characterization of a novel tissue-specific isoform, RNPDE4A8. 855 32

cGMP phosphodiesterase, a key enzyme in phototransduction, is composed of P alpha beta and two P gamma S. P gamma has two functions in P alpha beta regulation: (I) an inhibitor of cGMP hydrolysis and (II) a stimulator of cGMP binding to their noncatalytic sites. Here we show for the first time that these functions can be discriminated. P gamma release by GTP-bound transducing from P alpha beta was stimulated by NaCl in a concentration-dependent manner. However, phosphodiesterase activity in membranes washed with NaCl-free buffer already reached the maximum level. [3H]-cGMP binding of P alpha beta in membranes washed with NaCl required more P gamma than that in membranes washed without NaCl. Other salts had a similar effect. Identical P gamma was released under different [NaCl]. These results indicate that P gamma for the function (I) is released in low [salt], but P gamma for the function (II) is released in high [salt]. These P gamma functions may be expressed separately in phototransduction.
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PMID:Discrimination of two functions of photoreceptor cGMP phosphodiesterase gamma subunit. 867 Feb 32

Congestive heart failure is a clinical syndrome producing symptomatic deterioration, functional impairment, and shortened life span. The syndrome is complex in that it includes both peripheral and cardiac effects which contribute to the progression of heart failure. In the periphery, elevations in the sympathetic nervous system and renin-angiotensin system increase afterload and contribute to further salt and water retention. The central cardiac abnormalities include remodeling of the heart and downregulation of beta receptors. Traditional heart failure therapy has included treatment of fluid retention with diuretics, although their effect on mortality has never been addressed. The most proven therapy in heart failure is treatment with vasodilators, particularly angiotensin-converting enzyme (ACE) inhibitors. Improved survival with ACE-inhibitor therapy has been demonstrated in patients with severe heart failure (CONSENSUS), mild to moderate heart failure (SOLVD), and in comparison with vasodilator therapy with hydralazine isosorbide dinitrate (VHeFT II). Improved survival has also been noted in postmyocardial infarction when the ejection fraction is decreased (SAVE). The ACE inhibitors have now become standard therapy for heart failure regardless of severity. Additive vasodilator therapy with calcium-channel antagonists is under investigation. Inotropic therapy is controversial at present because of disappointing mortality results. The clinical mainstay digitalis remains without convincing mortality reduction data. Other inotropic agents, particularly phosphodiesterase inhibitors, have shown uniformly negative survival results. However, the new mixed action agents vesnarinone and pimobenden have shown favorable data, with vesnarinone demonstrating a mortality reduction effect. Beta-blocker therapy in heart failure has also found renewed interest, particularly with the new agents carvedolol and bucindolol which also have vasodilating properties.
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PMID:Pharmacologic treatment of congestive heart failure. 870 66

Recent research on cellular mechanisms of peripheral taste has defined transduction pathways involving membrane receptors, G proteins, second messengers, and ion channels. Receptors for organic tastants received much attention, because they provide the specificity of a response. Their future cloning will constitute a major advance. Taste transduction typically utilizes two or more pathways in parallel. For instance, sweet-sensitive taste cells of the rat appear to respond to sucrose with activation of adenylyl cyclase, followed by adenosine 3',5'-cyclic monophosphate (cAMP)-dependent membrane events and Ca2+ uptake. The same cells respond differently to some artificial sweeteners, i.e., with activation of phospholipase C (PLC) followed by inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release from intracellular stores. Some bitter tastants block K+ channels or initiate the cascade receptor G1 protein, PLC, IP3, and Ca2+ release or the cascade receptor alpha-gustducin, phosphodiesterase (PDE), cAMP decrease, and opening of cAMP-blocked channels. Membrane-permeant bitter tastants may elicit a cellular response by interacting with G protein, PLC, or PDE of the above cascades. Salt taste is initiated by current flowing into the taste cell through cation channels located in the apical membrane, even though basolateral channels may also contribute (following salt diffusion through paracellular pathways). In rodents, the Na+-specific component of salt taste is typically mediated by apical amiloride-sensitive Na+ channels, but less specific and not amiloride-sensitive taste components exist in addition. Sour taste may in part be mediated by amiloride-sensitive Na+ channels conducting protons, but other mechanisms certainly contribute. Thus the transduction of taste cells generally comprises parallel pathways. Furthermore, the transduction pathways vary with the location of taste buds on the tongue and, of course, across species of animals. To identify these pathways, to understand how they are controlled and why they evolved to this complexity are major goals of present research.
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PMID:Taste reception. 875 87

Nanterinone (UK-61,260) is a novel positive inotropic and balanced-type vasodilating drug, only partially based on phosphodiesterase III inhibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety. As its acute hemodynamic effects in humans are unknown, an oral dose of 2 mg nanterinone was studied in 14 patients with heart failure (NYHA class II-III) on chronic diuretic and angiotensin-converting enzyme (ACE) inhibitor treatment. Before the study, patients were on a 2 g salt-balanced diet, and they received their last medication 16 hours before each study day. Hemodynamic measurements were carried out before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours after administration of the study drug. All patients received placebo and nanterinone on 2 consecutive days. Following nanterinone, systemic vascular resistance decreased immediately from 1699 +/- 82 (mean +/- SEM) at baseline to 1368 +/- 80 at 1 hour. Changes persisted for 12 hours. Concomitantly, there was an immediate and significant fall in pulmonary wedge pressure to 38% of baseline at 1.5 hours, together with a 20% reduction in pulmonary artery pressure. Heart rate remained unchanged and arterial pressures showed only a short, significant decrease. Cardiac index rose significantly from 2.28 +/- 0.15 at baseline to a highest value of 2.65 +/- 0.14 1/min/m2 at 1 hour. Changes persisted for 3 hours. Placebo had no effect on these variables. As, in view of its potential venodilating properties, hemodynamic improvement by nanterinone may depend on pre-existing left ventricular filling pressure, patients were subsequently grouped according to baseline pulmonary wedge pressure of > 12 mmHg (H-PCWP) and < or = 12 mmHg (L-PCWP). Cardiac index improved by 26% in H-PCWP and by 17% in L-PCWP (NS). In contrast, PCWP fell more markedly in H-PWCP than in L-PCWP (40% and 23%, respectively, p < 0.05). Thus, oral nanterinone results in a significant acute hemodynamic improvement and is well tolerated. Although changes in left ventricular filling pressure are more pronounced in patients with elevated pre-existing PCWP, cardiac pump function improves equally in patients with normal or low left ventricular filling pressure at baseline.
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PMID:Acute hemodynamic effects and preload-dependent cardiovascular profile of the partial phosphodiesterase inhibitor nanterinone in patients with mild to moderate heart failure. 884 5

Hypoxanthine can block preimplantation mouse embryo development in vitro at the 2- to 4-cell stages, and this has recently been shown to be reversed by cAMP-elevating agents. However, the extent of this hypoxanthine-induced arrest is determined by the culture conditions and strain of mouse. Whitten's and KSOM/AA are two embryo culture media that support preimplantation development to the blastocyst stage. This study was undertaken to examine the influence of several components in these media on hypoxanthine-arrested preimplantation mouse embryos and to test the hypothesis that reversal of the hypoxanthine block by cAMP-elevating agents requires cooperative interaction with the chelator, EDTA. Initial experiments demonstrated that embryo development was blocked in the presence of hypoxanthine in Whitten's medium but not in KSOM/AA; furthermore, removal of EDTA from KSOM/AA rendered this medium incapable of supporting high levels of development to blastocyst (9%), whereas high numbers of blastocysts (80%) formed in Whitten's medium, which does not contain the chelator. Consequently, Whitten's medium was used to test our hypothesis. It has previously been demonstrated that the phosphodiesterase inhibitor, IBMX, can reverse the developmental arrest imposed by hypoxanthine in EDTA-supplemented Earle's basic salt solution, but in the present study the addition of IBMX to Whitten's medium resulted in a block to development and failed to reverse the hypoxanthine arrest. These disparate effects can be explained by the presence or absence of EDTA. Supplementing Whitten's medium with EDTA reverses the IBMX effect, but not the hypoxanthine-induced block. While IBMX alone is unable to reverse the hypoxanthine block in Whitten's medium, development is greatly enhanced by the simultaneous addition of EDTA and IBMX. Similar results were obtained with the cAMP analogue, 8-AHA-cAMP. The data therefore support our hypothesis that the reversal of the hypoxanthine-induced arrest by cAMP-elevating agents is critically dependent on the presence of EDTA. We contrast this with the situation in mouse oocytes, where the hypoxanthine-induced meiotic arrest is not reversed by the addition of EDTA and/or cAMP-elevating agents.
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PMID:Cyclic AMP reversal of hypoxanthine-arrested preimplantation mouse embryos is EDTA-dependent. 891 26

1. Protein kinase modulation of gamma-aminobutyric acid-A (GABAA)- and glycine-activated Cl- currents in freshly dissociated, morphologically identified rabbit retinal rod bipolar cells was studied under voltage clamp with the use of the whole cell patch-clamp technique. Responses to pulses of GABA and glycine were monitored before, during, and after application of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) and protein kinase C (PKC) activators, inactive analogues, and inhibitors. 2. Bath perfusion with either forskolin, an adenylate cyclase activator, or its inactive analogue, 1,9 dideoxyforskolin, reduced the GABA-activated Cl- currents by 30-50%; coapplication of N-[2-(Methylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (H-8), a PKA inhibitor, did not prevent the forskolin effects. The membrane-permeable cAMP analogues, 8-bromo-cAMP and 8-(4-Chlorophenylthio)-cAMP, and intracellularly dialyzed cAMP, did not modulate either the GABA- or glycine-activated Cl- current. Perfusion of the phosphodiesterase inhibitor 3-isobutyl-1-methylxantine (IBMX) had no direct effect on the GABA-activated current and did not alter the results with cAMP or its membrane-permeable analogues. Collectively, these results make it very unlikely that PKA represents an important mechanism of either GABAA or glycine channel modulation in the rabbit rod bipolar cell. 3. Although the isoquinoline sulfonamide protein kinase inhibitor H-8 was without discernible effect, the related compounds 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochlorine (H-7) and N-(2-Aminoethyl)-5-isoquinolinesulfonamide dihydrochloride (H-9) both dramatically reduced the GABA response. H-7 also strongly reduced the response to glycine, whereas H-8 had no effect and H-9 had an intermediate effect. Because only certain members of this inhibitor class of agents proved effective, and their effectiveness appeared unrelated to the established activity profiles, these agents probably inhibit the Cl- currents in a phosphorylation-independent manner. Direct interaction of these inhibitors with binding sites in the GABAA receptor-channel complex has been previously reported in some other preparations. 4. The phorbol ester and PKC activator phorbol 12,13 dibutyrate (PDB) led to a 35-55% reduction in the GABA-activated Cl- current of the rod bipolar cell. The broad-spectrum kinase inhibitor staurosporine, and the more PKC-specific inhibitor calphostin C, had no direct effect on GABA responses, but prevented Cl- current reduction when coapplied with PDB. Phorbol 12-myristate 13-acetate (PMA) reduced the GABA-activated current in a fashion very similar to PDB. Staurosporine and calphostin C blocked the PMA effect. No reduction of Cl- current was seen with the inactive analogue, 4-alpha-PMA, used as a control for PKC-independent phorbol ester effects. 5. PDB effectively reduced the GABA-activated Cl- current of the rod bipolar cell at low concentrations, whereas PMA had a diminished effect at low concentrations. This is consistent with the reported concentration-dependent abilities of these agents to promote translocation of PKC-alpha immunoreactivity from the membrane to the cytosolic compartment in the rabbit retinal rod bipolar cell. Collectively, the data from phorbol esters, inactive analogues, and kinase inhibitors support the existence of a PKC-mediated mechanism for GABA-activated Cl- current reduction in these cells. 6. The naphthalenesulfonamide PKC activator N-(n-Heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) also potently and reversibly reduced the GABA-activated current. Staurosporine and calphostin C eliminated this effect. When the nonhydrolyzable guanosine 5'-triphosphate (GTP) analogue guanosine 5'-O-(3-thiotriphosphate) tetralithium salt (GTP-gamma-S) replaced GTP in the recording pipette, the SC-10-mediated GABA current reduction became irreversible.(ABSTRACT TRUNCATED)
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PMID:Protein kinase modulation of GABAA currents in rabbit retinal rod bipolar cells. 893 Feb 56

The integrity of the mesothelial layer is essential for both defence and solute transport in continuous ambulatory peritoneal dialysis (CAPD). The human peritoneal mesothelial cell (HPMC) culture has been shown to be a very useful tool to study the peritoneal mesothelial stem cell behaviour. We investigated whether hydralazine, an antihypertensive agent frequently used, might affect HPMC growth and collagen synthesis. HPMCs were cultured from specimens of human omentum by enzymatic disaggregation of omentum. HPMC growth was evaluated by modified methyltetrazolium (MTT) assay. Cell viability was confirmed by trypan blue exclusion and lactate dehydrogenase assay. Collagen synthesis was measured by 3H-proline incorporation into pepsin-resistant, salt-precipitated collagen. Intracellular cAMP levels were measured by enzyme immunoassay. The procollagen alpha 1 (I) mRNA expression was evaluated by Northern blot analysis. Hydralazine inhibited serum-stimulated HPMC growth in a dose-dependent manner. The maximal inhibition was 93% at a concentration of 100 micrograms/ml. Hydralazine inhibited collagen synthesis in confluent mesothelial cells (47% inhibition at a concentration of 100 micrograms/ml). The procollagen alpha 1 (I) mRNA expression was also decreased by hydralazine (about 50% decrease at 100 micrograms/ml). These effects may be due to the phosphodiesterase inhibition property of hydralazine to increase intracellular cAMP levels. These data suggest that the use of hydralazine in CAPD patients may affect peritoneal membrane function and integrity.
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PMID:Hydralazine inhibits human peritoneal mesothelial cell proliferation and collagen synthesis. 894 90

The development of targeted, bidentate photoaffinity reagents for mapping the interacting domains of calmodulin (CaM) with the enzymes that it regulates required the synthesis and evaluation of the binding affinity of various phenothiazines. These photoaffinity reagents would possess a photoactive 3-azidophenothiazine group for cross-linking the hydrophobic binding domain of CaM, a second photoactive benzophenone group that would be activated at a different wavelength than the 3-azidophenothiazine group, and a suitable radiolabel. Difficulties were encountered in identifying those structural features that would be compatible with the introduction of a benzophenone group, with the solubility of these benzophenone-substituted phenothiazines, and with the ability of these phenothiazines to inhibit the calmodulin-mediated activation of phosphodiesterase. Solutions to this problem involved the preparation of phenothiazines possessing a quaternary ammonium salt, a zwitterionic amino acid, or a carbohydrate moiety. The phenothiazines that possessed photoactive 3-azido and benzophenone groups and in which one of the piperazine nitrogens in the side chain was converted to a quaternary, N-methylammonium iodide inhibited the calmodulin-mediated activation of phosphodiesterase at a level comparable to that of chlorpromazine.
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PMID:Synthesis and binding affinity of bidentate phenothiazines with two different photoactive groups. 897 55


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