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Ectonucleotide pyrophosphatase/phosphodiesterase family member 1 is an enzyme that in humans is encoded by the ENPP1 gene. This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5 triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with Idiopathic infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. Ectonucleotide pyrophosphatase/phosphodiesterase 1 has been shown to interact with Insulin receptor. GRCh38: Ensembl release 89: ...
Calmodulin-dependent phosphodiesterase (CaMPDE) is one of the key enzymes involved in the complex interactions which occur between the cyclic-nucleotide and Ca2+ second-messenger systems. Calmodulin-dependent phosphodiesterase exists in different isoenzymic forms, which exhibit distinct molecular and/or catalytic properties. The kinetic properties suggest that the 63 kDa brain isoenzyme is distinct from the brain 60 kDa and heart and lung CaMPDE isoenzymes. The CaMPDE isoenzymes of 60 kDa from brain, heart and lung are regulated by calmodulin, but the affinities for calmodulin are different. At identical concentrations of calmodulin, the bovine heart CaMPDE isoenzyme is stimulated at a much lower Ca2+ concentration than the bovine brain or lung isoenzymes. The bovine lung CaMPDE isoenzyme contains calmodulin as a tightly bound subunit, so that a change in calmodulin concentration had no effect on the [Ca2+]-dependence of activation of this isoenzyme. These observations are consistent with the ...
Treatment of intact hepatocytes with glucagon led to the rapid desensitization of adenylate cyclase, which reached a maximum around 5 min after application of glucagon, after which resensitization ensued. Complete resensitization occurred some 20 min after the addition of glucagon. In hepatocytes which had been preincubated with the cyclic AMP phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), glucagon elicited a stable desensitized state where resensitization failed to occur even 20 min after exposure of hepatocytes to glucagon. Treatment with IBMX alone did not elicit desensitization. The action of IBMX in stabilizing the glucagon-mediated desensitized state was mimicked by the non-methylxanthine cyclic AMP phosphodiesterase inhibitor Ro-20-1724 [4-(3-butoxy-4-methoxylbenzyl)-2-imidazolidinone]. IBMX inhibited the resensitization process in a dose-dependent fashion with an EC50 (concn. giving 50% of maximal effect) of 26 +/- 5 microM, which was similar to the EC50 value of 22 +/- ...
TY - JOUR. T1 - Cyclic nucleotide phosphodiesterase profiling reveals increased expression of phosphodiesterase 7B in chronic lymphocytic leukemia. AU - Zhang, Lingzhi. AU - Murray, Fiona. AU - Zahno, Anja. AU - Kanter, Joan R.. AU - Chou, Daisy. AU - Suda, Ryan. AU - Fenlon, Michael. AU - Rassenti, Laura. AU - Cottam, Howard. AU - Kipps, Thomas J.. AU - Insel, Paul A.. PY - 2008/12/9. Y1 - 2008/12/9. N2 - Cyclic nucleotide phosphodiesterase (PDE) isoforms can influence disease pathogenesis and be novel therapeutic targets. Because lower cAMP levels may contribute to the decreased apoptosis that occurs in chronic lymphocytic leukemia (CLL), we assessed the expression levels of PDE isoforms in peripheral blood mononuclear cells (PBMC) of healthy adults and patients with CLL. We found a unique PDE mRNA signature in CLL: higher levels than in normal PBMC of PDE7B (increased approximate to 23-fold) and lower levels of PDE3B, 4D, 5A, and 9A mRNA (each decreased approximate to 30-fold). Increased ...
Purpose: : Leber congenital amaurosis (LCA) is a common cause of infantile blindness. Here we study one LCA subtype caused by a mutation in the gene encoding the aryl hydrocarbon receptor-interacting protein like 1 (AIPL1). AIPL1 is an FK506-binding homolog specifically expressed in photoreceptor cells. Previous studies suggest that AIPL1 serves as a specialized chaperone for the synthesis of rod cGMP phosphodiesterase (PDE6) in photoreceptor cells. However, it is not yet clear whether AIPL1 primarily serves as a quantity control or a quality control. To address this question, we co-express AIPL1 and subunits of PDE6 followed by biochemical characterization. Methods: : To introduce AIPL1 into HEK293 cells, an AIPL1 HEK 293 stable cell line was established. Plasmids expressing PDE6 subunits were then transduced into HEK293 cells and the AIPL1 HEK293 stable cell line, respectively. Immunoblotting was used to determine the expression levels for PDE6 subunits. SDS-PAGE followed by immunoblotting was ...
The 2020 Gordon Research Seminar on Cyclic Nucleotide Phosphodiesterases (GRS) will be held in Les Diablerets, Switzerland. Apply today to reserve your spot.
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3,5-cyclic-AMP phosphodiesterases, 3,5-cyclic-GMP phosphodiesterases, animals, cyclic GMP, cyclic nucleotide phosphodiesterases, type 1, cyclic nucleotide phosphodiesterases, type 5, enzyme activation, GTP-binding proteins, guanylyl imidodiphosphate, isoenzymes, lung, muscle, smooth, phosphoric diester hydrolases, phosphorylation, protein kinases, signal transduction, Pharmacy and materia medica, ...
Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, cGMP, phosphodiesterase, cone, photoreceptor, signal transduction, cDNA, polyclonal antibody, mRNA expression, ground squirrel, ROD CGMP-PHOSPHODIESTERASE, PHOTORECEPTOR CELLS, CONE PHOTORECEPTORS, BETA-SUBUNIT, S-ANTIGEN, RD MOUSE, CDNA, DEGENERATION, EXPRESSION, GENES ...
1. A simple new assay for glycerylphosphorylcholine phosphodiesterase is described, in which radioactive glycerylphosphorylcholine is used as substrate and the reaction products are separated by adsorption on an anion-exchange resin. 2. Rat liver subcellular fractions contained both particulate (58%) and soluble (42%) glycerylphosphorylcholine phosphodiesterase. Both activities released free choline from glycerylphosphorylcholine. 3. The particulate glycerylphosphorylcholine phosphodiesterase was recovered mainly in the nuclear and microsomal fractions and showed a distribution similar to those of 5′-nucleotidase and alkaline phosphodiesterase I, both of which are constituents of the liver plasma membrane. 4. During purification of plasma membranes glycerylphosphorylcholine phosphodiesterase, 5′-nucleotidase and alkaline phosphodiesterase I showed largely similar behaviour, indicating that glycerylphosphorylcholine phosphodiesterase is also localized in liver plasma membranes. Slight ...
The existence of cyclic GMP phosphodiesterase (EC 3.1.4.-) was demonstrated in silkworm larva by gel filtration of the homogenate. The cyclic GMP phosphodiesterase was separated from cyclic AMP phosphodiesterases by column chromatography on hydroxyapatite and Sephadex G-200. The enzyme ...read more ...
Sigma-Aldrich offers abstracts and full-text articles by [Marcelo L Santoro, Tais S Vaquero, Adriana F Paes Leme, Solange M T Serrano].
K12316 GAA; lysosomal alpha-glucosidase [EC:3.2.1.20] K00963 UGP2; UTP--glucose-1-phosphate uridylyltransferase [EC:2.7.7.9] K00963 UGP2; UTP--glucose-1-phosphate uridylyltransferase [EC:2.7.7.9] K01513 ENPP1_3; ectonucleotide pyrophosphatase/phosphodiesterase family member 1/3 [EC:3.1.4.1 3.6.1.9] K05349 bglX; beta-glucosidase [EC:3.2.1.21] K05349 bglX; beta-glucosidase [EC:3.2.1.21] K05349 bglX; beta-glucosidase [EC:3.2.1.21] K05349 bglX; beta-glucosidase [EC:3.2.1.21] K05349 bglX; beta-glucosidase [EC:3.2.1.21] K01225 CBH1; cellulose 1,4-beta-cellobiosidase [EC:3.2.1.91] K01225 CBH1; cellulose 1,4-beta-cellobiosidase [EC:3.2.1.91] K00693 GYS; glycogen synthase [EC:2.4.1.11] K00750 GYG1; glycogenin [EC:2.4.1.186] K00750 GYG1; glycogenin [EC:2.4.1.186] K00750 GYG1; glycogenin [EC:2.4.1.186] K00750 GYG1; glycogenin [EC:2.4.1.186] K00700 GBE1; 1,4-alpha-glucan branching enzyme [EC:2.4.1.18] K00688 PYG; glycogen phosphorylase [EC:2.4.1.1] K01196 AGL; glycogen debranching enzyme [EC:2.4.1.25 ...
This study shows that in vitro exposure to high glucose (i.e., 25 mmol/L) of platelets from healthy subjects reduces the antiaggregating action of aspirin, an effect blunted by the antioxidant agent amifostine. It also shows that high glucose does not affect the ability of aspirin to inhibit thromboxane synthesis but impairs the ability of aspirin to activate the NO/cGMP/PKG pathway. Furthermore, it demonstrates that high glucose per se does not influence platelet aggregation in response to agonists, thromboxane synthesis, and the NO/cGMP/PKG pathway.. Thus, high glucose reduces the antiaggregating properties of aspirin only at very high concentrations; the extent of inhibition, although significant, is modest. In our experimental conditions, we did not observe the dramatic dose-dependent inhibition of platelet sensitivity to aspirin described by other authors (17,19).. Is it possible to translate results obtained in vitro to in vivo conditions? It is interesting to observe that the lack of ...
Bis-(3-5)-cyclic dimeric guanosine monophosphate (c-di-GMP) is a bacterial second messenger that regulates multiple cellular behaviors in most major bacterial phyla. C-di-GMP signaling in bacterial often includes enzymes that are responsible for the synthesis and degradation of c-di-GMP, effector proteins or molecules that bind c-di-GMP, and targets that interact with effectors. However, little is known about the specificity of c-di-GMP signaling in controlling virulence and bacterial behaviors. In this work, we have investigated the c-di-GMP signaling network using the model plant pathogen Dickeya dadantii 3937. In Chapter 2, we characterized two PilZ domain proteins that regulate biofilm formation, swimming motility, Type III secretion system (T3SS) gene expression, and pectate lyase production in high c-di-GMP level conditions. YcgR3937 binds c-di-GMP both in vivo and in vitro. Next, we revealed a sophisticated regulatory network that connects the sRNA, c-di-GMP signaling, and flagellar master
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CO and 4 of the CORMs (ALF 153, 157, 436 and CORM-2) increased cGMP levels in smooth muscle cells, while the rest of the compounds failed to alter cGMP production. The CORM-stimulated increase was minor (50-300% over basal) compared to the effects seen with the NO-donor, SNP (at least 100-fold). CORM-3, a widely used CORM, decreased basal cGMP levels in RASMC. Interestingly, CO and CORMs modestly reduced SNP-stimulated cGMP formation in RASMC. The inactive forms of CORMs (compounds lacking the ability to liberate CO) did not affect SNP-induced cGMP accumulation. CORMs also reduced bradykinin-stimulated cGMP levels in endothelial-smooth muscle co-cultures. In sGC activity assays using purified recombinant human sGC, CORMs were ineffective in stimulating cGMP production. However, CORMs blocked up to 80% of DEA-NO-induced sGC activity. ...
Although South Carolina is home to many types of spiders, most are harmless to people. Brown recluse spiders are an exception to this thanks to their potentially fatal bites. Its important for you to know more about these spiders, including what they look like and when to get help from Hilton Head Island pest control services.. Brown Recluse Spiders in SC. Brown recluse spiders havent always been in SC, but theyve been in our state since 1976. Over the years, they have continued to spread throughout SC and are now found in all counties.. How to Identify Brown Recluse Spiders. Brown recluse spiders can be difficult to spot. These spiders arent big, and they dont have highly noticeable coloring. As adults, they grow to around 3/4 of an in inch. These spiders usually have a light brown or yellowish coloring and a violin shape on their back.. Brown Recluse Spider Behavior. Brown recluse spiders do not spin webs in corners or other areas where they might be easier to spot. Instead, these spiders ...
The mechanisms of growth factor action were studied in a fibroblastic cell line capable of reversible growth arrest in G0-G1. This cell line, derived from Chinese hamster lung, can be stimulated to divide by a limited set of purified growth factors, including EGF, FGF, PDGF, x-thrombin (THR), serotonin (5-HT) and insulin. THR and 5-HT stimulate, via a G-protein (Gp), a polyphosphoinositide-specific phospholipase C (PtdIns(4,5)P2-PLC). In contrast, the mitogens EGF, FGF, PDGF, and insulin do not stimulate PtdIns(4,5)P2-PLC, unless this pathway has been preactivated by THR or AIF4. Finally, from the specific inhibitory action of pertussis toxin on THR- and 5-HT-induced DNA synthesis, and from the exploitation of the 5-HT pharmacological tools, we conclude that: (i) there are at least two distinct Gproteins involved in signalling growth: Gp, coupling receptors to PtdIns(4,5)P2-PLC, and G1 coupling receptors negatively to adenylyl cyclase and probably to other unknown effector(s); (ii) activation of ...
cAMP-specific 3,5-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene. This gene is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family. Cyclic nucleotides are important second messengers that regulate and mediate a number of cellular responses to extracellular signals, such as hormones, light, and neurotransmitters. The cyclic nucleotide phosphodiesterases (PDEs) regulate the cellular concentrations of cyclic nucleotides and thereby play a role in signal transduction. This gene encodes a protein that specifically hydrolyzes cAMP. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. Altered activity of this protein has been associated with schizophrenia and bipolar disorder. PDE4B is believed to be the PDE4 subtype involved in the antipsychotic effects of PDE4 inhibitors such as rolipram. PDE4B is involved in dopamine-associated and stress-related behaviours. It has ...
cAMP-specific 3,5-cyclic phosphodiesterase 4C is an enzyme that in humans is encoded by the PDE4C gene. PDE4C is predominantly found in peripheral tissues. GRCh38: Ensembl release 89: ENSG00000105650 - Ensembl, May 2017 "Human PubMed Reference:". "Mouse PubMed Reference:". "Entrez Gene: PDE4C phosphodiesterase 4C, cAMP-specific (phosphodiesterase E1 dunce homolog, Drosophila)". Zhang, HT (2009). "Cyclic AMP-Specific Phosphodiesterase-4 as a Target for the Development of Antidepressant Drugs". Current Pharmaceutical Design. 15 (14): 1688-1698. doi:10.2174/138161209788168092. PMID 19442182. Engels P, Sullivan M, Müller T, Lübbert H (1995). "Molecular cloning and functional expression in yeast of a human cAMP-specific phosphodiesterase subtype (PDE IV-C)". FEBS Lett. 358 (3): 305-10. doi:10.1016/0014-5793(94)01460-I. PMID 7843419. Milatovich A, Bolger G, Michaeli T, Francke U (1994). "Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse". Somat. Cell Mol. ...
TY - JOUR. T1 - Phosphorylation of tyrosine hydroxylase by cyclic GMP - Dependent protein kinase. AU - Roskoski, R.. AU - Vulliet, Philip R. AU - Glass, D. B.. PY - 1987. Y1 - 1987. N2 - Tyrosine hydroxylase purified from rat pheochromycytoma was phosphorylated and activated by purified cyclic GMP-dependent protein kinase as well as by cyclic AMP-dependent protein kinase catalytic subunit. The extent of activation was correlated with the degree of phosphate incorporated into the enzyme. Comparable stoichiometric ratios (0.6 mol phosphate/mol tyrosine hydroxylase subunit) were obtained at maximal concentrations of either cyclic AMP-dependent or cyclic GMP-dependent protein kinases. The enzymes appeared to mediate the phosphorylation of the same residue based on the observation that incorporation was not increased when both enzymes were present. The major tryptic phosphopeptide obtained from tyrosine hydroxylase phosphorylated by each protein kinase exhibited an identical retention time following ...
TY - JOUR. T1 - C-type natriuretic peptide/guanylate cyclase B system in ATDC5 cells, a chondrogenic cell line. AU - Suda, Michio. AU - Tanaka, Kiyoshi. AU - Yasoda, Akihiro. AU - Komatsu, Yasato. AU - Chusho, Hideki. AU - Miura, Masako. AU - Tamura, Naohisa. AU - Ogawa, Yoshihiro. AU - Nakao, Kazuwa. PY - 2002/12/1. Y1 - 2002/12/1. N2 - Natriuretic peptides constitute a family of three structurally related peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Particulate guanylate cyclases, GC-A, and GC-B, are the receptors for these peptides to mediate their action. ANP and BNP possess high affinities for GC-A, and CNP is the preferred ligand for GC-B. In this article, we report our study of the expression and possible role(s) of natriuretic peptides in ATDC5 cells, which represent a chondrogenic cell line. ATDC5 cells produced cyclic guanosine monophosphate (cGMP) in response to natriuretic peptides. CNP was far more potent than ANP ...
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NMDA and nitric oxide act through the cGMP signal transduction pathway to repress hypothalamic gonadotropin-releasing hormone gene expression.s profile, publications, research topics, and co-authors
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0139] The dosage forms of the invention can be employed for the treatment and prevention of all diseases regarded as treatable or preventable through the use of PDE 4 inhibitors. Selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (specifically of type 4) are suitable on the one hand as bronchial therapeutic agents (for the treatment of airway obstructions owing to their dilating effect but also owing to their effect increasing the respiratory rate and respiratory drive) and for eliminating erectile dysfunction owing to the vasodilating effect, but on the other hand especially for the treatment of disorders, especially of an inflammatory nature, e.g. of the airways (asthma prophylaxis), of the skin, of the central nervous system, of the intestine, of the eyes and of the joints, which are promoted by mediators such as histamine, PAF (platelet-activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines, alpha-, beta- and ...
TY - JOUR. T1 - Cyclic GMP injected into retinal rod outer segments increases latency and amplitude of response to illumination. AU - Nicol, G. D.. AU - Miller, W. H.. PY - 1978/1/1. Y1 - 1978/1/1. N2 - The authors have injected cyclic GMP intracellularly by iontophoresis through the recording electrode into single rod outer segments of the isolated superfused retina of the toad, Bufo marinus. The two most marked effects of the injection are: (i) the latency of the hyperpolarizing membrane-potential change caused by illumination is increased from 5 to 50 times normal, the increase in latency being inversely proportional to the light stimulus intensity; and (ii) the amplitude of the hyperpolarizing receptor potential is increased. These effects are reversible. The authors findings are consistent with the hypothesis that cyclic GMP is a link in the molecular chain of events that controls the inward flow of sodium ions in light and darkness. The increased latency the authors observe after injection ...
Lysine vasopressin (antidiuretic hormone), like cyclic adenosine 3,5-monophosphate (cyclic AMP), rapidly (in less than 1 hour) stimulates the initiation of deoxyribonucleic acid synthesis and thereby increases the flow of cells into mitosis in rat thymic lymphocyte populations in vitro. This mitogenic action of vasopressin, again like that of cyclic AMP, is potentiated by caffeine, an inhibitor of the intracellular phosphodiesterase which catalyzes the degradation of cyclic AMP. On the other hand, vasopressins mitogenic action (also like that of cyclic AMP) is blocked by imidazole, an activator of cyclic nucleotide phosphodiesterase activity. The hormone, thyrocalcitonin (calcitonin) which is known to block the cyclic AMP-mediated mitogenic effect of parathyroid hormone by interfering with cyclic AMP action, also blocks the mitogenic action of vasopressin. The inhibitory effects of imidazole and thyrocalcitonin on vasopressins mitogenic action are both overcome by the phosphodiesterase inhibitor
As mentioned above, RyRs are often complexed with several accessory proteins, forming an intricate multi-protein array [32, 33]. The best known RyR-interacting proteins are CaM, which tonically inhibits RyR2 activity and produces biphasic effects on RyR1 [34, 35]; FKBP12 and FKBP12.6, which stabilize RyR1 and RyR2 closures [36-38]; and the ternary complex triadin-junctin-calsequestrin, which senses luminal Ca2+ content and modulates RyR activity by acting either as a Ca2+ reservoir or as a direct channel ligand [39-47]. More recently, RyR2 has been found to hold anchoring sites for protein kinase (PK)A, protein phosphatase (PP)1, the cAMP-specific phosphodiesterase (PDE)4D3 and Ca2+/calmodulin-dependent protein kinase (CaMK)II [37, 48], emphasizing the importance of RyR2 regulation by phosphorylation [32]. In cardiac cells, sorcin exerts protein-protein interactions with the RyR and inhibits Ca2+ release in a Ca2+-dependent manner [49, 50].. The binding sites of several regulatory proteins ...
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TY - JOUR. T1 - Human C-type natriuretic peptide. AU - Ogawa, Yoshihiro. AU - Nakao, Kazuwa. AU - Nakagawa, Osamu. AU - Komatsu, Yasato. AU - Hosoda, Kiminori. AU - Suga, Shin Ichi. AU - Arai, Hiroshi. AU - Nagata, Kiyoshi. AU - Yoshida, Nobuo. AU - Imura, Hiroo. PY - 1992/6. Y1 - 1992/6. N2 - We isolated the human C-type natriuretic peptide gene and identified the peptide in the brain. The human C-type natriuretic peptide gene appeared to be composed of at least two exons and one intron. In the 5′-flanking region, there is an array of cis elements (an inverted CCA AT box, two GC boxes, and a cyclic AMP response element-like sequence) that is not present in upstream sequences of the atrial and brain natriuretic peptide genes. Analysis of the deduced amino acid sequence revealed that human prepro C-type natriuretic peptide comprises 126 amino acids and that the C-terminal 22-residue peptide (G-L-S-K-G-C-F-G-L-K-L-D-R-I-G-S-M-S-G-L-G-C) preceded by Lys-Lys is identical to the porcine ...
Minami N, Suzuki Y, Yamamoto M, Kihira H, Imai E, Wada H, Kimura Y, Ikeda Y, Shiku H, Nishikawa M.; Inhibition of shear stress-induced platelet aggregation by cilostazol, a specific inhibitor of cGMP-inhibited phosphodiesterase, in vitro and ex vivo.; Life Sci. , 1997 PubMed Europe PMC ...
The cyclic nucleotides cAMP and cGMP are common signaling molecules synthesized in neurons following the activation of adenylyl or guanylyl cyclase. In the striatum, the synthesis and degradation of cAMP and cGMP is highly regulated as these second messengers have potent effects on the activity of striatonigral and striatopallidal neurons. This review will summarize the literature on cyclic nucleotide signaling in the striatum with a particular focus on the impact of cAMP and cGMP on the membrane excitability of striatal medium-sized spiny output neurons (MSNs). The effects of non-selective and selective phosphodiesterase (PDE) inhibitors on membrane activity and synaptic plasticity of MSNs will also be reviewed. Lastly, this review will discuss the implications of the effects PDE modulation on electrophysiological activity of striatal MSNs as it relates to the treatment of neurological disorders such as Huntingtons and Parkinsons disease.
TY - JOUR. T1 - Prevention of nitric oxide synthase induction in vascular smooth muscle cells by microtubule depolymerizing agents. AU - Marczin, Nándor. AU - Papapetropoulos, Andreas. AU - Jilling, Tamás. AU - Catravas, John D.. PY - 1993/1/1. Y1 - 1993/1/1. N2 - We investigated the role of microtubules in the induction of nitric oxide synthase in cultured vascular smooth muscle cells. We found that like interleukin‐1α, lipopolysaccharide elicited a time and concentration‐dependent accumulation of cyclic GMP via induction of nitric oxide synthase. Nocodazole and colchicine, two chemically distinct microtubule depolymerizing agents, completely prevented lipopolysaccharide‐ and interleukin‐induced (and nitric oxide‐mediated) cyclic GMP generation. In contrast to lipopolysaccharide and interleukin‐1α, cyclic GMP accumulation in response to sodium nitroprusside, an exogenous nitrovasodilator, was not altered by either nocodazole or colchicine. Our findings demonstrate that ...
The photoreceptor 3´:5´-cyclic nucleotide phosphodiesterase (PDE) is the central enzyme of visual excitation in rod photoreceptors. The hydrolytic activity of PDE is precisely regulated by its inhibitory g subunit (Pg), which binds directly to the catalytic site. We examined the inhibition of frog rod outer segment PDE by endogenous Pg, as well as by synthetic peptides corresponding to its central and C-terminal domains, to determine whether the non-catalytic cGMP-binding sites on the catalytic ab dimer of PDE allosterically regulate PDE activity. We found that the apparent binding affinity of Pg for PDE was 28 pM when cGMP occupied the non-catalytic sites, whereas Pg had an apparent affinity only 1/16 of this when the sites were empty. The elevated basal activity of PDE with empty non-catalytic sites can be decreased by the addition of nanomolar levels of cGMP, demonstrating that the high-affinity non-catalytic sites on the PDE catalytic dimer mediate this effect. No evidence for a direct allosteric
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Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. Has a high affinity for both cAMP and cGMP.
Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that degrade the cyclic nucleotides cAMP and cGMP, and play a key role in modulating the amplitude and duration of the signal delivered by these two key intracellular second messengers. Defects in cyclic nucleotide signalling are known to be involved in several pathologies. As a consequence, PDEs have long been recognized as potential drug targets, and they have been the focus of intense research for the development of therapeutic agents. A number of PDE inhibitors are currently available for the treatment of disease, including obstructive pulmonary disease, erectile dysfunction, and heart failure. However, the performance of these drugs is not always satisfactory, due to a lack of PDE-isoform specificity and their consequent adverse side effects. Recent advances in our understanding of compartmentalised cyclic nucleotide signalling and the role of PDEs in local regulation of cAMP and cGMP signals offers the opportunity for the development
In bullfrog (Rana catesbiana) rods the activity of cyclic GMP (cGMP) phosphodiesterase was stimulated 10 times by washing disc membranes with an isotonic, GTP-containing buffer. This stimulation was maintained following hydrolysis of GTP and after removal of guanine nucleotides. At least 60-70% of the inhibitory gamma subunit of cGMP phosphodiesterase (P gamma) was physically released from membranes by these washing procedures. When cGMP phosphodiesterase was activated by a hydrolysis-resistant GTP analogue, P gamma was found in the supernatant complexed with the transducin alpha subunit (T alpha) using three chromatography systems. When GTP was used to activate cGMP phosphodiesterase, P gamma was also found in the supernatant complexed with GDP.T alpha. This complex was also isolated using the same three chromatography systems, indicating that P gamma remained tightly bound to T alpha even after bound GTP was hydrolyzed. Interaction with the beta,gamma subunits of transducin, which remained associated
Sphingomyelin phosphodiesterase D (EC 3.1.4.41, sphingomyelinase D) is an enzyme of the sphingomyelin phosphodiesterase family with systematic name sphingomyelin ceramide-phosphohydrolase. These enzymes catalyse the hydrolysis of sphingomyelin, resulting in the formation of ceramide 1-phosphate and choline: sphingomyelin + H2O ⇌ {\displaystyle \rightleftharpoons } ceramide 1-phosphate + choline or the hydrolysis of 2-lysophosphatidylcholine to give choline and 2-lysophosphatidate. Sphingomyelin phosphodiesterase D activity is shared by enzymes with a wider substrate range, classified as phospholipases D or lipophosphodiesterase II EC 3.1.4.4. Sphingomyelinases D are produced by some spiders in their venoms, by arthropods such as ticks, or pathogenic bacteria and fungi. Pathogenicity is expressed through different mechanisms, such as membrane destabilization, cell penetration, inflammation of the lungs and cutaneous lesions, common following spider bites. Sphingomyelin phosphodiesterase Carne, ...
Endotoxin stimulates leukocytes to release cytokines that initiate septic shock in humans and animals. CD14, a glycosyl-phosphatidylinositol-anchored membrane glycoprotein, is an endotoxin receptor on leukocytes, and endotoxin binding to CD14 induces cytokine production. Here we show that glycosyl-phosphatidylinositol-anchored or integral membrane CD14 mediates identical cellular responses to endotoxin, including NF-kappa B activation and protein tyrosine phosphorylation. We also show that an anti-CD14 monoclonal antibody that does not block endotoxin binding to CD14 nonetheless inhibits cell activation by endotoxin. These findings suggest that binding of endotoxin to cell-surface CD14 is followed by subsequent interactions of the endotoxin-CD14 complex with additional membrane component(s) that enable transmembrane signaling. This function of CD14 may be prototypic for other members of the glycosyl-phosphatidylinositol-anchored family of proteins that do not play a primary role in signal ...
Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction processes mediated by cAMP and cGMP. One PDE family member, PDE3B, plays an important role in the regulation of a variety of metabolic processes such as lipolysis and insulin secretion. In this study, the cellular localization and the role of PDE3B in the regulation of triglyceride, cholesterol and glucose metabolism in hepatocytes were investigated. PDE3B was identified in caveolae, specific regions in the plasma membrane, and smooth endoplasmic reticulum. In caveolin-1 knock out mice, which lack caveolae, the amount of PDE3B protein and activity were reduced indicating a role of caveolin-1/caveolae in the stabilization of enzyme protein. Hepatocytes from PDE3B knock out mice displayed increased glucose, triglyceride and cholesterol levels, which was associated with increased expression of gluconeogenic and lipogenic genes/enzymes including, phosphoenolpyruvate carboxykinase, peroxisome ...
TY - JOUR. T1 - Original Research. T2 - Role of phosphodiesterases in modulation of BK Ca channels in hypertensive pulmonary arterial smooth muscle. AU - Zhu, Shu. AU - White, Richard E.. AU - Barman, Scott A. PY - 2008/1/1. Y1 - 2008/1/1. N2 - BK Ca channels regulate pulmonary arterial pressure, and protein kinase C (PKC) inhibits BK Ca channels, but little is known about PKC-mediated modulation of BK Ca channel activity in pulmonary arterial smooth muscle. Studies were carried out to determine mechanisms of PKC modulation of BK Ca channel activity in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR), an animal model of pulmonary hypertension. Forskolin opened BK Ca channels in FHR PASMC, which was blocked by PKC activation, and reversed by the phosphodiesterase (PDE) inhibitors IBMX, milrinone, and zaprinast. PDE inhibition also blocked the vasoconstrictor response to PKC activation in FHR pulmonary arteries. These results indicate that PKC inhibits cAMP-induced ...
TY - JOUR. T1 - Rapid assay for cyclic AMP and cyclic GMP phosphodiesterases. AU - Rangel-Aldao, Rafael. AU - Schwartz, David. AU - Rubin, Charles S.. PY - 1978/7/1. Y1 - 1978/7/1. N2 - A rapid highly sensitive assay for cyclic AMP phosphodiesterase has been devised. After a 5-min incubation, cyclic AMP is readily resolved from 5′-AMP, adenosine, and inosine by ion-exchange thin-layer chromatography on 1.3 × 6.5-cm strips of PEI-cellulose for 7 to 8 min. This procedure combines the accuracy of the standard paper chromatography assay (1) with the speed of ion-exchange resin techniques (2), while surmounting some of the major drawbacks of the other two methods (3). Since chromatography on PEI-cellulose efficiently resolves cyclic GMP, 5′-GMP, and guanosine, this methodology has also been adapted to the measurement of cyclic GMP hydrolysis.. AB - A rapid highly sensitive assay for cyclic AMP phosphodiesterase has been devised. After a 5-min incubation, cyclic AMP is readily resolved from ...
Rhodopsin is the protein found in retinas that converts light into a molecular signal that is eventually transmitted to the brain as a nerve signal. It is located in the disks in the outer segments of rod cells. When a photon is absorbed by the proteins chromophore, retinal, it undergoes a cis-trans conformational change. This structural change is carried out in the context of the protein structure and generates a change in structure on the cytoplasmic side of the protein than causes it to interact with the G-protein, transducin. A series of intermolecular interactions involving the Transducin alpha subunit and a phosphodiesterase eventually causes a reduction in the levels of c-GMP and the associated closing of ion channels in the rod cells. This causes the cells to polarize and starts the nervous signal. We have recently solved the three-dimensional structure of rhodopsin (Science, 289, 739-745 (2000)). Much work remains to structurally characterize the various photostates of the molecule and ...
Myomegalin has been characterized as a protein with the properties of a scaffold or structural protein that is expressed at high levels in skeletal and cardiac tissue, suggesting an important function in muscle, and which interacts with a cAMP-specific phosphodiesterase [13]. However, the precise function and interactions of this protein, and its five isoforms, have been largely unknown. We here describe how the smallest MMGL isoform, isoform 4, binds to known and predicted PKA targets in the cardiac myocyte, including some sarcomeric proteins, viz. cMyBPC, cTNI, ENO1, ENO3, CARP and COMMD4 (Tables 1 and 2). Moreover, we show that MMGL isoform 4 interacts with two regulatory subunits of PKA (Figure 3). Together these results describe MMGL isoform 4 as a novel sarcomeric AKAP, which, like mAKAP [14], is involved in assembling a PKA/PDE cAMP signalling module.. In addition to interacting with both types of regulatory subunits, viz. RI and RII, which qualifies MMGL isoform 4 as a dual-specific AKAP ...
In an adult, cerebral blood flow is typically 750 millilitres per minute or 15% of the cardiac output. Vinpocetine enhances cerebral blood flow by dilating blood vessels and reducing blood viscosity. Vinpocetine enhances cerebral metabolism by helping to maintain healthy blood flow and oxygen utilization. ...