Cyclic nucleotide phosphodiesterases type 1. Medical search

A CALCIUM and CALMODULIN-dependent cyclic nucleotide phosphodiesterase subfamily. The three members of this family are referred to as type 1A, type 1B, and type 1C and are each product of a distinct gene. In addition, multiple enzyme variants of each subtype can be produced due to multiple alternative mRNA splicing. Although the type 1 enzymes are classified as 3',5'-cyclic-AMP phosphodiesterases (EC 3.1.4.17), some members of this class have additional specificity for CYCLIC GMP.

Enzymes that catalyze the hydrolysis of CYCLIC AMP to form adenosine 5'-phosphate. The enzymes are widely distributed in animal tissue and control the level of intracellular cyclic AMP. Many specific enzymes classified under this heading demonstrate additional spcificity for 3',5'-cyclic IMP and CYCLIC GMP.

A cyclic nucleotide phosphodiesterase subfamily that is found predominantly in inflammatory cells and may play a role in the regulation of CELL-MEDIATED IMMUNITY. The enzyme family includes over twenty different variants that occur due to multiple ALTERNATIVE SPLICING of the mRNA of at least four different genes.

A cyclic nucleotide phosphodiesterase subfamily that is inhibited by the binding of CYCLIC GMP to an allosteric domain found on the enzyme and through phosphorylation by regulatory kinases such as PROTEIN KINASE A and PROTEIN KINASE B. The two members of this family are referred to as type 3A, and type 3B, and are each product of a distinct gene. In addition multiple enzyme variants of each subtype can be produced due to multiple alternative mRNA splicing.

A cyclic nucleotide phosphodiesterase subfamily that is activated by the binding of CYCLIC GMP to an allosteric domain found on the enzyme. Multiple enzyme variants of this subtype can be produced due to multiple alternative mRNA splicing. The subfamily is expressed in a broad variety of tissues and may play a role in mediating cross-talk between CYCLIC GMP and CYCLIC CMP pathways. Although the type 2 enzymes are classified as 3',5'-cyclic-AMP phosphodiesterases (EC 3.1.4.17), members of this class have additional specificity for CYCLIC GMP.

A class of enzymes that catalyze the hydrolysis of one of the two ester bonds in a phosphodiester compound. EC 3.1.4.

Nucleoside-2',3'-cyclic phosphate nucleotidohydrolase. Enzymes that catalyze the hydrolysis of the 2'- or 3'- phosphate bonds of 2',3'-cyclic nucleotides. Also hydrolyzes nucleoside monophosphates. Includes EC 3.1.4.16 and EC 3.1.4.37. EC 3.1.4.-.

Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases.

Enzymes that catalyze the hydrolysis of cyclic GMP to yield guanosine-5'-phosphate.

A cyclic nucleotide phosphodiesterase subfamily that is highly specific for CYCLIC GMP. It is found predominantly in vascular tissue and plays an important role in regulating VASCULAR SMOOTH MUSCLE contraction.

Guanosine cyclic 3',5'-(hydrogen phosphate). A guanine nucleotide containing one phosphate group which is esterified to the sugar moiety in both the 3'- and 5'-positions. It is a cellular regulatory agent and has been described as a second messenger. Its levels increase in response to a variety of hormones, including acetylcholine, insulin, and oxytocin and it has been found to activate specific protein kinases. (From Merck Index, 11th ed)

A cyclic nucleotide phosphodiesterase subfamily that is highly specific for CYCLIC AMP. Several isoforms of the enzyme type exist, each with its own tissue localization. The isoforms are encoded by at least two genes and are a product of multiple alternative splicing of their mRNAs.

An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.

A phosphodiesterase 4 inhibitor with antidepressant properties.

A potent cyclic nucleotide phosphodiesterase inhibitor; due to this action, the compound increases cyclic AMP and cyclic GMP in tissue and thereby activates CYCLIC NUCLEOTIDE-REGULATED PROTEIN KINASES

Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.

Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.

A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels.

The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.

The rate dynamics in chemical or physical systems.

A cyclic nucleotide phosphodiesterase subfamily that is highly specific for CYCLIC GMP. It is found predominantly in the outer segment PHOTORECEPTOR CELLS of the RETINA. It is comprised of two catalytic subunits, referred to as alpha and beta, that form a dimer. In addition two regulatory subunits, referred to as gamma and delta, modulate the activity and localization of the enzyme.

The monomeric units from which DNA or RNA polymers are constructed. They consist of a purine or pyrimidine base, a pentose sugar, and a phosphate group. (From King & Stansfield, A Dictionary of Genetics, 4th ed)

Compounds that specifically inhibit PHOSPHODIESTERASE 3.

Compounds that specifically inhibit PHOSPHODIESTERASE 4.

Inhibitor of phosphodiesterases.

N-(1-Oxobutyl)-cyclic 3',5'-(hydrogen phosphate)-2'-butanoate guanosine. A derivative of cyclic GMP. It has a higher resistance to extracellular and intracellular phosphodiesterase than cyclic GMP.

A methyl xanthine derivative from tea with diuretic, smooth muscle relaxant, bronchial dilation, cardiac and central nervous system stimulant activities. Theophylline inhibits the 3',5'-CYCLIC NUCLEOTIDE PHOSPHODIESTERASE that degrades CYCLIC AMP thus potentiates the actions of agents that act through ADENYLYL CYCLASES and cyclic AMP.

A phosphoric diester hydrolase that removes 5'-nucleotides from the 3'-hydroxy termini of 3'-hydroxy-terminated OLIGONUCLEOTIDES. It has low activity towards POLYNUCLEOTIDES and the presence of 3'-phosphate terminus on the substrate may inhibit hydrolysis.

A subgroup of cyclic nucleotide-regulated ION CHANNELS within the superfamily of pore-loop cation channels. They are expressed in OLFACTORY NERVE cilia and in PHOTORECEPTOR CELLS and some PLANTS.

Enzymes that catalyze the cleavage of a phosphorus-oxygen bond by means other than hydrolysis or oxidation. EC 4.6.

A positive inotropic cardiotonic agent with vasodilator properties. It inhibits cAMP phosphodiesterase type 3 activity in myocardium and vascular smooth muscle. Milrinone is a derivative of amrinone and has 20-30 times the inotropic potency of amrinone.

A cyclic nucleotide derivative that mimics the action of endogenous CYCLIC AMP and is capable of permeating the cell membrane. It has vasodilator properties and is used as a cardiac stimulant. (From Merck Index, 11th ed)

A group of compounds that are derivatives of oxo-pyrrolidines. A member of this group is 2-oxo pyrrolidine, which is an intermediate in the manufacture of polyvinylpyrrolidone. (From Merck Index, 11th ed)

A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.

A group of cyclic GMP-dependent enzymes that catalyze the phosphorylation of SERINE or THREONINE residues of proteins.

An enzyme of the lyase class that catalyzes the formation of CYCLIC AMP and pyrophosphate from ATP. EC 4.6.1.1.

Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system.

An alkaloid found in opium but not closely related to the other opium alkaloids in its structure or pharmacological actions. It is a direct-acting smooth muscle relaxant used in the treatment of impotence and as a vasodilator, especially for cerebral vasodilation. The mechanism of its pharmacological actions is not clear, but it apparently can inhibit phosphodiesterases and it may have direct actions on calcium channels.

Inosine cyclic 3',5'-(hydrogen phosphate). An inosine nucleotide which acts as a mild inhibitor of the hydrolysis of cyclic AMP and cyclic GMP and as an inhibitor of cat heart cyclic AMP phosphodiesterase.

The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.

Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant COLEUS FORSKOHLII. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland.

An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2.

The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.

A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.

Compounds that specifically inhibit PHOSPHODIESTERASE 5.

A long-acting derivative of cyclic AMP. It is an activator of cyclic AMP-dependent protein kinase, but resistant to degradation by cyclic AMP phosphodiesterase.

A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.

Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.

The process of cleaving a chemical compound by the addition of a molecule of water.

Isopropyl analog of EPINEPHRINE; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant.

Purine bases found in body tissues and fluids and in some plants.

The parts of a macromolecule that directly participate in its specific combination with another molecule.

The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.

The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.

A group of indole-indoline dimers which are ALKALOIDS obtained from the VINCA genus of plants. They inhibit polymerization of TUBULIN into MICROTUBULES thus blocking spindle formation and arresting cells in METAPHASE. They are some of the most useful ANTINEOPLASTIC AGENTS.

Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.

A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.

The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.

Involvement of phosphodiesterase-cGMP-PKG pathway in intracellular Ca2+ oscillations in pituitary GH3 cells. (1/146)

The present study investigates the potential role of the Ca2+-calmodulin-dependent type I phosphodiesterase (PDE)-cGMP-protein kinase G (PKG) pathway in spontaneous [Ca2+]i oscillations in GH3 cells using fura-2 single cell videoimaging. Vinpocetine (2.5-50 microM), a selective inhibitor of type I PDE, induced a concentration-dependent inhibition of spontaneous [Ca2+]i oscillations in these pituitary cells, and at the same time produced an increase of the intracellular cGMP content. The cell permeable cGMP analog N2,2'-O-dibutyryl-cGMP (dB-cGMP) (1 mM) caused a progressive reduction of the frequency and the amplitude of spontaneous [Ca2+]i oscillations when added to the medium. KT5823 (400 nM), a selective inhibitor of cGMP-dependent protein kinase (PKG), produced an increase of baseline [Ca2+]i and the disappearance of spontaneous [Ca2+]i oscillations. When KT5823 was added before vinpocetine, the PKG inhibitor counteracted the [Ca2+]i lowering effect of the cGMP catabolism inhibitor. Finally, the removal of extracellular Ca2+ or the blockade of L-type voltage-sensitive calcium channels (VSCC) by nimodipine produced a decrease of cytosolic cGMP levels. Collectively, the results of the present study suggest that spontaneous [Ca2+]i oscillations in GH3 cells may be regulated by the activity of type I PDE-cGMP-PKG pathway. (+info)

Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. (2/146)

The effects of several phosphodiesterase (PDE) inhibitors on the L-type Ca current (I(Ca)) and intracellular cyclic AMP concentration ([cAMP]i) were examined in isolated rat ventricular myocytes. The presence of mRNA transcripts encoding for the different cardiac PDE subtypes was confirmed by RT-PCR. IBMX (100 microM), a broad-spectrum PDE inhibitor, increased basal I(Ca) by 120% and [cAMP]i by 70%, similarly to a saturating concentration of the beta-adrenoceptor agonist isoprenaline (1 microM). However, MIMX (1 microM), a PDE1 inhibitor, EHNA (10 microM), a PDE2 inhibitor, cilostamide (0.1 microM), a PDE3 inhibitor, or Ro20-1724 (0.1 microM), a PDE4 inhibitor, had no effect on basal I(Ca) and little stimulatory effects on [cAMP]i (20-30%). Each selective PDE inhibitor was then tested in the presence of another inhibitor to examine whether a concomitant inhibition of two PDE subtypes had any effect on I(Ca) or [cAMP]i. While all combinations tested significantly increased [cAMP]i (40-50%), only cilostamide (0.1 microM)+ Ro20-1724 (0.1 microM) produced a significant stimulation of I(Ca) (50%). Addition of EHNA (10 microM) to this mix increased I(Ca) to 110% and [cAMP]i to 70% above basal, i.e. to similar levels as obtained with IBMX (100 microM) or isoprenaline (1 microM). When tested on top of a sub-maximal concentration of isoprenaline (1 nM), which increased I(Ca) by (approximately 40% and had negligible effect on [cAMP]i, each selective PDE inhibitor induced a clear stimulation of [cAMP]i and an additional increase in I(Ca). Maximal effects on I(Ca) were approximately 8% for MIMX (3 microM), approximately 20% for EHNA (1-3 microM), approximately 30% for cilostamide (0.3-1 microM) and approximately 50% for Ro20-1724 (0.1 microM). Our results demonstrate that PDE1-4 subtypes regulate I(Ca) in rat ventricular myocytes. While PDE3 and PDE4 are the dominant PDE subtypes involved in the regulation of basal I(Ca), all four PDE subtypes determine the response of I(Ca) to a stimulus activating cyclic AMP production, with the rank order of potency PDE4>PDE3>PDE2>PDE1. (+info)

The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. (3/146)

To understand the role cAMP phosphodiesterases (PDEs) play in the regulation of insulin secretion, we analyzed cyclic nucleotide PDEs of a pancreatic beta-cell line and used family and isozyme-specific PDE inhibitors to identify the PDEs that counteract glucose-stimulated insulin secretion. We demonstrate the presence of soluble PDE1C, PDE4A and 4D, a cGMP-specific PDE, and of particulate PDE3, activities in betaTC3 insulinoma cells. Selective inhibition of PDE1C, but not of PDE4, augmented glucose-stimulated insulin secretion in a dose-dependent fashion thus demonstrating that PDE1C is the major PDE counteracting glucose-dependent insulin secretion from betaTC3 cells. In pancreatic islets, inhibition of both PDE1C and PDE3 augmented glucose-dependent insulin secretion. The PDE1C of betaTC3 cells is a novel isozyme possessing a K(m) of 0.47 microM for cAMP and 0.25 microM for cGMP. The PDE1C isozyme of betaTC3 cells is sensitive to 8-methoxymethyl isobutylmethylxanthine and zaprinast (IC(50) = 7.5 and 4.5 microM, respectively) and resistant to vinpocetine (IC(50) > 100 microM). Increased responsiveness of PDE1C activity to calcium/calmodulin is evident upon exposure of cells to glucose. Enhanced cAMP degradation by PDE1C, due to increases in its responsiveness to calcium/calmodulin and in intracellular calcium, constitutes a glucose-dependent feedback mechanism for the control of insulin secretion. (+info)

Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11. (4/146)

1. The cyclic nucleotide phosphodiesterases (PDEs) present in an insulin secreting cell line, BRIN - BD11, were characterized using calcium/calmodulin, IGF-1, isoenzyme-selective PDE inhibitors and RT - PCR. 2. Calmodulin activated cyclic AMP or cyclic GMP PDE activity in pellet and was 3 fold (P=0.002) more potent in activating cyclic nucleotide hydrolysis in pellet compared with supernatant fractions. 3. The PDE1/PDE5 inhibitor zaprinast inhibited both cyclic AMP and cyclic GMP PDE activity in both pellet and supernatant fractions of cell homogenates by a maximum of around 25% (IC(50) 1 - 5 microM), while rolipram (PDE4 selective) inhibited only cyclic AMP hydrolysis. 4. The PDE3-selective inhibitors Org 9935 (0.02 - 10 microM) and siguazodan (0.1 - 10 microM) inhibited cyclic AMP PDE activity in the pellet but not the supernatant fractions of cell homogenates, with a maximum inhibition of about 30%. IGF-1 (2 - 7.5 ng ml(-1)) potently augmented this PDE activity. 5. RT - PCR using specific primers for PDE3B, but not for PDE3A, amplified, from BRIN - BD11 cell total RNA, a 351 base pair product that was >97% homologous with rat adipose tissue PDE3B. 6. IBMX, Org 9935, siguazodan and rolipram (1 - 50 microM), but not zaprinast, each augmented glucose-induced insulin secretion in the presence of 16.7 mM but not 1 mM glucose. 7. These findings, in a clonal insulin secreting cell line, are consistent with an important role for PDE3B in regulating the pool of cyclic AMP relevant to the modulation of glucose-induced insulin secretion. (+info)

Differential inhibition of multiple cAMP phosphodiesterase isozymes by isoflavones and tyrphostins. (5/146)

A series of isoflavone and tyrphostin compounds were found to inhibit the degradation of cAMP by several cyclic nucleotide phosphodiesterase (PDE) isozymes. Specific hydroxyl groups on the isoflavone structure were critical for PDE isozyme-selective inhibition. Replacement of the C-7 hydroxyl group of the isoflavone with a methoxy group raised the IC(50) for PDE1, PDE3, and PDE4. The absence of the C-5 hydroxyl group raised the IC(50) from 5 to >100 microM for PDE4, but actually lowered the IC(50) for PDE3 and PDE1. Replacement of the C-4' hydroxyl group with a methoxy group raised the IC(50) for PDE3 and PDE1, yet only slightly changed the IC(50) for PDE4. Various tyrphostins were also potent inhibitors of PDE1, PDE3, and PDE4. The four-carbon side chained tyrphostins were much less potent; however, a very interesting pattern was observed in which removal of phenolic hydroxyls on the tyrphostin structure increased the potency for PDE1 and PDE3, but not PDE4. These results may help to explain some of the therapeutic and intracellular signaling effects of isoflavones and tyrphostins. Moreover, the isozyme selectivity demonstrated by the isoflavones and tyrphostins can serve as a pharmacophore for the design of specific PDE inhibitors. (+info)

Differential changes in the expression of cyclic nucleotide phosphodiesterase isoforms in rat brains by chronic treatment with electroconvulsive shock. (6/146)

Electroconvulsive shock (ECS) has been suggested to affect cAMP signaling pathways to exert therapeutic effects. ECS was recently reported to increase the expression of PDE4 isoforms in rat brain, however, these studies were limited to PDE4 family in the cerebral cortex and hippocampus. Thus, for comprehensive understanding of how ECS regulates PDE activity, the present study was performed to determine whether chronic ECS treatment induces differential changes in the expression of all the PDE isoforms in rat brains. We analyzed the mRNA expression of PDE isoforms in the rat hippocampus and striatum using reverse transcription polymerase chain reaction. We found chronic ECS treatment induced differential changes in the expression of PDE isoform 1, 2, 3, 4, 5 and 7 at the rat hippocampus and striatum. In the hippocampus, the expression of PDE1A/B (694%), PDE4A (158%), PDE4B (323 %), and PDE4D (181%) isoforms was increased from the controls, but the expression of PDE2 (62.8%) and PDE7 (37.8%) decreased by chronic ECS treatment. In the striatum, the expression of PDE1A/B (179%), PDE4A (223%), PDE4B (171%), and PDE4D (327%) was increased by chronic ECS treatment with the concomitant decrease in the expression of PDE2 (78.4%) and PDE3A (67.1%). In conclusion, chronic ECS treatment induces differential changes in the expression of most PDE isoforms including PDE1, PDE2, PDE3, PDE4, PDE5, and PDE7 in the rat hippocampus and striatum in an isoform- and brain region-specific manner. Such differential change is suggested to play an important role in regulation of the activity of PDE and cAMP system by ECS. (+info)

"cAMP-specific" phosphodiesterase contributes to cGMP degradation in cerebellar cells exposed to nitric oxide. (7/146)

Nitric oxide (NO) functions as a diffusible messenger in the central nervous system and elsewhere, exerting many of it physiological effects by activating soluble guanylyl cyclase, so increasing cellular cGMP levels. Hydrolysis of cyclic nucleotides is achieved by phosphodiesterases (PDEs) but the enzyme isoforms responsible for degrading cGMP in most cells have not been identified. We have devised a method for quantitatively monitoring the rate of breakdown of cGMP within intact cells and have applied it to rat cerebellar cell suspensions previously stimulated with NO. In contrast to previous findings in cultured cerebellar cells, there was no evidence from the use of selective inhibitors that PDE 1 participated importantly in cGMP hydrolysis. Moreover, procedures expected to increase PDE 1 activity by raising cytosolic Ca2+ concentrations (neurotransmitter agonists, Ca2+ ionophore) failed to influence cGMP breakdown. Instead, through the use of inhibitors selective for different PDE families, two isoforms were implicated: a "cGMP-specific" PDE (PDE 5), inhibited by sildenafil and zaprinast, and a "cAMP-specific" PDE (PDE 4), inhibited by low concentrations of rolipram and Ro-20-1724 and by milrinone. An explanation is offered for a participation of PDE 4 based on the high estimated intracellular cGMP concentration (approximately 800 microM) and the low affinity of the enzyme for cGMP. In accordance with predictions, recombinant PDE 4 was shown to hydrolyze high cGMP concentrations in a rolipram-sensitive manner. The widespread use of rolipram to test for a specific involvement of cAMP in cellular phenomena must therefore be questioned. (+info)

Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. (8/146)

From a series of benzamide derivatives, roflumilast (3-cyclo-propylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) was identified as a potent and selective PDE4 inhibitor. It inhibits PDE4 activity from human neutrophils with an IC(50) of 0.8 nM without affecting PDE1 (bovine brain), PDE2 (rat heart), and PDE3 and PDE5 (human platelets) even at 10,000-fold higher concentrations. Roflumilast is almost equipotent to its major metabolite formed in vivo (roflumilast N-oxide) and piclamilast (RP 73401), however, more than 100-fold more potent than rolipram and Ariflo (cilomilast; SB 207499). The anti-inflammatory and immunomodulatory potential of roflumilast and the reference compounds was investigated in various human leukocytes using cell-specific responses: neutrophils [N-formyl-methyl-leucyl-phenylalanine (fMLP)-induced formation of LTB(4) and reactive oxygen species (ROS)], eosinophils (fMLP- and C5a-induced ROS formation), monocytes, monocyte-derived macrophages, and dendritic cells (lipopolysaccharide-induced tumor necrosis factor-alpha synthesis), and CD4+ T cells (anti-CD3/anti-CD28 monoclonal antibody-stimulated proliferation, IL-2, IL-4, IL-5, and interferon-gamma release). Independent of the cell type and the response investigated, the corresponding IC values (for half-maximum inhibition) of roflumilast were within a narrow range (2-21 nM), very similar to roflumilast N-oxide (3-40 nM) and piclamilast (2-13 nM). In contrast, cilomilast (40-3000 nM) and rolipram (10-600 nM) showed greater differences with the highest potency for neutrophils. Compared with neutrophils and eosinophils, representing the terminal inflammatory effector cells, the relative potency of roflumilast and its N-oxide for monocytes, CD4+ T cells, and dendritic cells is substantially higher compared with cilomilast and rolipram, probably reflecting an improved immunomodulatory potential. The efficacy of roflumilast in vitro and in vivo (see accompanying article in this issue) suggests that roflumilast will be useful in the treatment of chronic inflammatory disorders such as asthma and chronic obstructive pulmonary disease. (+info)

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1. The cyclic nucleotide phosphodiesterases (PDEs) present in an insulin secreting cell line, BRIN - BD11, were characterized using calcium/calmodulin, IGF-1, isoenzyme-selective PDE inhibitors and RT - PCR. (strath.ac.uk)
Cyclic nucleotide phosphodiesterases (PDEs) constitute a family of enzymes that degrade cAMP and cGMP. (cdc.gov)
Intracellular cyclic nucleotide levels increase in response to extracellular stimulation by hormones, neurotransmitters, or growth factors and are down-regulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. (cdc.gov)
Some PDEs such as type 4 are specific for cAMP, while others such PDE5, specific for cGMP ( Beavo, 1995 ). (frontiersin.org)
However, each of the main kinetoplastid parasites express four class 1-type cyclic nucleotide-specific phosphodiesterases (PDEA-D), which have highly similar catalytic domains to that of human PDEs. (gla.ac.uk)
1 The synthesis and degradation of cyclic-AMP are tightly controlled by 2 classes of enzymes, adenylyl cyclases and phosphodiesterases (PDEs), respectively. (bloodjournal.org)
8 These and other studies 9,10 also underlined the importance of cAMP phosphodiesterases (PDEs) for the spatiotemporal control of cAMP signals. (ahajournals.org)
2,3 Cyclic GMP is degraded by cGMP-hydrolyzing phosphodiesterases (PDEs). (ahajournals.org)
6 Like NO, cGMP can affect multiple signaling pathways ( Figure 1 A). 1,5,6 To date, three classes of cGMP receptor proteins have been identified: cyclic nucleotide-gated (CNG) cation channels, cGMP-regulated PDEs, which hydrolyze cAMP and/or cGMP, and cGMP-dependent protein kinases (cGKs). (ahajournals.org)
This project aims to unite global efforts to target the highly druggable class of enzymes called cyclic nucleotide phosphodiesterases (PDEs) in the fight for neglected parasitic diseases (NPD). (europa.eu)
cGMP-driven activation of protein kinases, ion channels, or phosphodiesterases (PDEs) causes a broad variety of physiological responses whereas dysregulation can result in severe pathologies. (springer.com)
Intracellular cAMP concentration is regulated by the activities of at least two families of enzymes: adenylyl and guanylyl cyclases, responsible for cAMP and cGMP synthesis and cyclic nucleotide phosphodiesterases (PDEs) that mediate cAMP and cGMP hydrolysis.Among the PDE superfamily, PDE2 is a dual substrate enzyme that hydrolyzes both cAMP and cGMP and has the unique property to be stimulated by cGMP. (worldcat.org)
The level of intracellular cAMP is controlled through its production by adenylyl cyclases and its breakdown by cyclic nucleotide phosphodiesterases (PDEs). (lu.se)
Functions of cyclic GMP include the regulation of cation channels and PDEs and activation of cyclic GMP-dependent protein kinase (PKG). (ersjournals.com)
PKG), cGMP-regulated phosphodiesterases (PDEs) and cyclic nucleotide-gated ion channels 4 . (ersjournals.com)
A-kinase anchoring proteins (AKAPs) and cyclic nucleotide phosphodiesterases (PDEs) are essential enzymes in the cyclic adenosine 3'-5' monophosphate (cAMP) signaling cascade. (mdpi.com)

Several other proteins such as cyclic nucleotide gated ion channels ( 1 ), phosphodiesterases (PDE) ( 2 ), and guanine nucleotide exchange factors (Epac) ( 3 ) bind cAMP. (mcponline.org)
NCS-1 is a member of the neuronal calcium sensor family, a class of EF hand containing calcium-myristoyl-switch proteins. (wikipedia.org)
Expression of FLAG-tagged transfected PKG1β (top panel) and HIV-1 viral proteins are shown by Western blotting. (biomedcentral.com)
Viral proteins expressed from the HIV-1 molecular clone were then measured. (biomedcentral.com)
The second messenger 3′,5′-cyclic adenosine monophosphate (cyclic-AMP) uses effector proteins to influence cell function and fate. (bloodjournal.org)
Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs), such as the photoreceptor RHO. (uniprot.org)
Using wild type (wt) and non-myristoylated mutant PKG II proteins it was demonstrated that N-myristoylation (N-myr) is important for targeting of PKG II to membranes and distal ends of filopodia like structures in COS-1 and HEK-293 cells. (ubc.ca)
Recent research has focused mainly on the cyclic GMP pathway and phosphodiesterase type 5 (PDE5, cyclic GMP specific PDE) in the control of vaginal vascular smooth muscle, whereas only little is known on the role of other key proteins and mediators of cyclic nucleotide mediated signaling in this process. (elsevier.com)
EPAC is a cAMP-activated guanine nucleotide exchange factor (cAMP-GEF) for the small GTP-binding proteins Rap1 and Rap2. (pubmedcentralcanada.ca)
Heterotrimeric guanine nucleotide-binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. (vwr.com)
None of the three universal stress proteins or nitroreductase, and a considerably lower amount of HspX was detected in carbon-starved wild-type cultures. (asm.org)
A tBLASTn search of the Myxococcus xanthus genome database at The Institute for Genomic Research (TIGR) identified three genes ( pdeA , pdeB , and pdeC ) that encode proteins homologous to 3′,5′-cyclic nucleotide phosphodiesterase. (asm.org)

Phosphodiesterase are enzymes that catalyze the hydrolysis of the 3′ cyclic phosphate bonds of adenosine and/or guanosine 3′, 5′ cyclic monophosphate ( Beavo, 1995 ). (frontiersin.org)
Although the type 1 enzymes are classified as 3',5'-cyclic-AMP phosphodiesterases (EC 3.1.4.17), some members of this class have additional specificity for CYCLIC GMP. (bvsalud.org)
Biochemical characterization of the inhibition of the two major phosphodiesterase isoenzymes in Drosophila by theophylline predicts only a slight inhibition of these enzymes in vivo , in accordance with the unchanged level of cAMP in wild-type fly heads during drug feeding. (springer.com)
The enzymes are widely distributed in animal tissue and control the level of intracellular cyclic AMP. (bvsalud.org)
Many specific enzymes classified under this heading demonstrate additional spcificity for 3',5'-cyclic IMP and CYCLIC GMP. (bvsalud.org)
1] Molecular biology of the cyclic AMP-specific cyclic nucleotide phosphodiesterases: a diverse family of regulatory enzymes. (axonmedchem.com)
The enzymes responsible for cGMP catabolism are the cyclic nucleotide phosphodiesterases, which catalyze the hydrolysis of cGMP and cAMP to the corresponding 5′-nucleotide monophosphate. (aspetjournals.org)
A number of diseases, including autosomal dominant hypertension with brachydactyly (HTNB) and type I long-QT syndrome (LQT1), result from mutations in genes encoding for distinct members of the two classes of enzymes. (mdpi.com)

3. The PDE1/PDE5 inhibitor zaprinast inhibited both cyclic AMP and cyclic GMP PDE activity in both pellet and supernatant fractions of cell homogenates by a maximum of around 25% (IC(50) 1 - 5 microM), while rolipram (PDE4 selective) inhibited only cyclic AMP hydrolysis. (strath.ac.uk)
Using phosphodiesterase type 5 (PDE5) inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. (frontiersin.org)
Manish, B. 3D QSAR, pharmacophore indentification studies on series of 1-(2-ethoxyethyl)-1H-pyrazolo[4,3-d] pyrimidines as PDE5 inhibitors. (eurekaselect.com)
Expression of three isoforms of cGMP-binding cGMP-specific phosphodiesterase (PDE5) in human penile cavernosum. (embl.de)
Inhibition of cGMP-specific phosphodiesterase type V (PDE5) has been shown to improve penile erection in patients with erectile dysfunction. (embl.de)
In the search for therapeutic strategies that engage the cGMP signalling pathway for the treatment of pulmonary arterial hypertension (PAH), inhibition of cGMP metabolism by phosphodiesterase type 5 (PDE5)-targeted compounds has proven most successful to date. (ersjournals.com)
In vascular smooth muscle cells, NO interacts with soluble guanylyl cyclase (sGC) to convert guanosine triphosphate (GTP) to cyclic GMP, which is hydrolysed and inactivated by phosphodiesterase type 5 (PDE5). (ersjournals.com)
PKG is the most important of these intracellular mediators, whereas the cGMP-regulated PDE type 5 (PDE5) is mainly responsible for modulating intracellular cGMP levels and PKG-dependent signalling produced by NO and natriuretic peptides 5 - 7 . (ersjournals.com)
In addition to these feedback mechanisms, there is the potential for gene regulation, as the promoter region of human PDE5 contains sites responsive to cyclic nucleotides 11 , 12 . (ersjournals.com)

Cyclic adenosine monophosphate phosphodiesterase type 4 protects against atrial arrhythmias. (nih.gov)
Phosphodiesterase 4 (PDE4) inhibition restores the suppressive effects of 3′,5′-cyclic adenosine monophosphate in lymphocytes. (bloodjournal.org)
1 The most common and versatile second messenger, cyclic adenosine monophosphate (cAMP), regulates a striking number of physiological and pathophysiological processes through the signaling networks which interfere with many disease states including inflammatory disorders, immune-deficiencies, and cancer. (pubmedcentralcanada.ca)
Our earliest understanding of phosphodiesterase (PDE) inhibitors began with a series of publications by Sutherland and Rall in the 1950s, describing the properties of cyclic adenosine monophosphate (cAMP). (beds.ac.uk)

Using a combination of electrophysiological and optical imaging techniques, we show here that vinpocetine, a PDE type I inhibitor, restores ocular dominance plasticity in the ferret model of fetal alcohol exposure. (jneurosci.org)
Here, we try to restore ocular dominance plasticity in alcohol-exposed ferrets using the PDE type 1 inhibitor vinpocetine. (jneurosci.org)
Roflumilast, type 4 phosphodiesterase inhibitor, attenuates inflammation in rats with ulcerative. (deepdyve.com)
El-Adawy, Samar A. 2018-03-01 00:00:00 BackgroundRoflumilast (Rof), a phosphodiesterase 4 (PDE4) inhibitor, has been shown to be an effective agent in inflammatory diseases and marketed for chronic obstructive pulmonary disease. (deepdyve.com)
Preimplant Phosphodiesterase-5 Inhibitor Use Is Associated With Higher Rates of Severe Early Right Heart Failure After Left Ventricular Assist Device Implantation. (harvard.edu)
Analysis of short-term treatment with the phosphodiesterase type 5 inhibitor tadalafil on long bone development in young rats. (harvard.edu)
Here, we show that the expression of a potential glucagon inhibitor, the adenosine A1 receptor (Adora1), is gradually diminished in α-cells of NOD mice, autoantibody-positive (AA + ) and overtly type 1 diabetic (T1D) patients during the progression of disease. (diabetesjournals.org)
Luo, H.B. Discovery of 3-(4-hydroxybenzyl)-1-(thiophen-2-yl)chromeno[2,3-c]pyrrol-9(2H)-one as a phosphodiesterase-5 inhibitor and its complex crystal structure. (eurekaselect.com)
Here, we review a decade-long exploration of the contribution of cyclic-AMP and PDE4 to the pathogenesis of B-cell lymphoma, 5 ⇓ ⇓ ⇓ - 9 culminating with the first-in-cancer clinical trial of a PDE4 inhibitor in advanced B-cell malignancies. (bloodjournal.org)
The effects of a novel Ca(2+)-sensitizer (EMD 60263, 10 microM, group 1) were compared with a phosphodiesterase (PDE) III-inhibitor (enoximon, 20 microM, group 2) on 14 isolated, blood-perfused rabbit hearts during reperfusion after a global ischemia of 20 min. (curehunter.com)
Pharmacological modulation of the in vivo induction of plasminogen activator inhibitor type-1 (PAI-1) synthesis was studied in rats using the induction of PAI-1 by endotoxin as a model system. (tudelft.nl)
Since five other lipoxygenase inhibitors, a phospholipase inhibitor, an inhibitor of leukotriene formation and dexamethasone had no effect on the endotoxin-induced increase in PAI-1 synthesis, the effect of BW755C could not be ascribed to its known pharmacological properties. (tudelft.nl)
In addition, induction of PAI was enhanced by isobutyl-methylxanthine, a phosphodiesterase inhibitor, but not, however, by other phosphodiesterase inhibitors, or by forskolin or N(G)-nitro-L-arginine, suggesting an effect of isobutyl-methylxanthine other than through cyclic nucleotides. (tudelft.nl)
Short-term or long-term treatments with a phosphodiesterase-4 (PDE4) inhibitor result in opposing agonist-induced Ca 2+ responses in endothelial cells. (unistra.fr)
Since the activity of the cyclic nucleotide is also regulated by phosphodiesterase 5, we have examined the effect of zaprinast, an inhibitor of the enzyme, on the sheep isolated internal anal sphincter. (bmj.com)
The cGMP PDE inhibitor zaprinast (1 mg/kg) selectively reversed the blunted CVP response to GTN in tolerant animals but had no effect on the CVP response to GTN in nontolerant animals or on the MAP response in either group. (aspetjournals.org)

Reduced nitric oxide - cyclic guanosine monophosphate (cGMP) signaling is observed in age-related vascular disease. (clinsci.org)
2 , 3 The therapeutic utility of controlling the intracellular levels of cyclic-AMP, and of cyclic guanosine monophosphate (cyclic-GMP), with PDE inhibitors is well established. (bloodjournal.org)
Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. (springer.com)
Transducin is a guanine nucleotide-binding protein found specifically in rod outer segments, where it mediates activation by rhodopsin of a cyclic GTP-specific (guanosine monophosphate) phosphodiesterase. (vwr.com)
Among the most important for pulmonary vascular homeostasis are factors that utilise cyclic guanosine monophosphate (cGMP) as an intracellular second messenger. (ersjournals.com)
Schematic diagram of the nitric oxide (NO)-cyclic guanosine monophosphate (GMP) signalling pathway. (ersjournals.com)
Two subtypes of natriuretic peptide receptor (NPR), NPR-A and NPR-B, are transmembrane guanylyl cyclases (particulate guanylyl cyclases), where the extracellular domain binds atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) or C-type natriuretic peptide and the intracellular domain hydrolyses guanosine triphosphate (GTP) to cGMP. (ersjournals.com)

6 Mechanistically, PDE4 inhibition resulted in elevation of intracellular cyclic-AMP levels and suppression of PI3K and AKT activity. (bloodjournal.org)
In this study, we examined the affects of NCS-1 on intracellular Ca 2+ and neurite outgrowth in cultured L. stagnalis snail PeA neurons. (biologists.org)
The enzyme is widely distributed in animal tissue and controls the level of intracellular cyclic AMP. (termsciences.fr)
Steady-state activation of cardiac β-adrenergic receptors leads to an intracellular compartmentation of cAMP resulting from localized cyclic nucleotide phosphodiesterase (PDE) activity. (ahajournals.org)
Two cyclic-nucleotide phosphodiesterases (DdPDE 1 and 2) have been identified previously, an extracellular dual-specificity enzyme and an intracellular cAMP-specific enzyme (encoded by the psdA and regA genes respectively). (embl.de)
Intracellular cyclic AMP (cAMP) levels of pdeA or pdeB mutant cells under these stressful conditions were about 1.3-fold to 2.0-fold higher than those of wild-type cells. (asm.org)
A cAMP phosphodiesterase gene ( cpdA )-disrupted Escherichia coli or Salmonella enterica serovar Typhimurium strain showed about 2- or 1.3-fold higher intracellular cAMP than the wild-type strain, respectively ( 2 , 6 ). (asm.org)

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. (wikipedia.org)
A cyclic nucleotide phosphodiesterase subfamily that is highly specific for CYCLIC GMP. (harvard.edu)
A cyclic nucleotide phosphodiesterase subfamily that is inhibited by the binding of CYCLIC GMP to an allosteric domain found on the enzyme and through phosphorylation by regulatory kinases such as PROTEIN KINASE A and PROTEIN KINASE B. The two members of this family are referred to as type 3A, and type 3B, and are each product of a distinct gene. (uams.edu)
A CALCIUM and CALMODULIN-dependent cyclic nucleotide phosphodiesterase subfamily. (bvsalud.org)

Most of the effects of the signaling molecule nitric oxide (NO) are mediated by cGMP, which is synthesized by soluble guanylyl cyclase and degraded by phosphodiesterases. (rupress.org)
Neurogenic relaxation of the internal anal sphincter is mediated by elevation of cyclic GMP, following activation of soluble guanylyl cyclase by nitric oxide. (bmj.com)
These include nitric oxide and the natriuretic peptide family (atrial, brain and C-type natriuretic peptides). (ersjournals.com)

Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. (frontiersin.org)
The aim of the present study was to evaluate in the human vagina, by means of immunohistochemistry, the expression and distribution of phosphodiesterase type 1 (PDE1, known to hydrolize both cyclic AMP and cyclic GMP) in relation to calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and protein gene product 9.5 (PGP 9.5). (elsevier.com)
Conclusion: Key mediators of the cyclic AMP and cyclic GMP pathways are co-localized in nerves seen in close proximity to vascular smooth muscle expressing PDE1. (elsevier.com)

Anchored PDE4 regulates chloride conductance in wild-type and ΔF508-CFTR human airway epithelia. (nih.gov)
6 These data linked the cyclic-AMP/PDE4 axis to the essential tonic BCR signals, highlighting the potential impact of PDE4 modulation in malignant B cells ( Figure 1 ). (bloodjournal.org)
Inhibition of PDE4 (with 10 μmol/L Ro 20-1724) increased the amplitude and dramatically slowed down the onset and recovery of cAMP signals, whereas PDE3 blockade (with 1 μmol/L cilostamide) had a minor effect only on subsarcolemmal cAMP. (ahajournals.org)

2. Calmodulin activated cyclic AMP or cyclic GMP PDE activity in pellet and was 3 fold (P=0.002) more potent in activating cyclic nucleotide hydrolysis in pellet compared with supernatant fractions. (strath.ac.uk)
An enzyme that catalyzes the hydrolysis of cyclic AMP to form adenosine 5'-phosphate. (termsciences.fr)

Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Ia Oxidation. (harvard.edu)
The principal target of cAMP is cAMP-dependent protein kinase (PKA) 1 . (mcponline.org)
No differences in activity or levels of cGMP-dependent protein kinase 1 or sGC were observed in Ercc1 d/- mice vs. WT. (clinsci.org)
The effect of cGMP (cyclic GMP) dependent protein kinase 1-β (PKG1-β) and cGMP analogues on transcriptional activity and replication of human immunodeficiency virus type 1 (HIV-1) was investigated. (biomedcentral.com)
Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. (forskningsdatabasen.dk)
A quantitative model for the kinetics of cAMP-dependent protein kinase (type II) activity. (springer.com)

Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes. (abcam.com)
By the 1960s, the role of cyclic nucleotide second messengers, such as cAMP, in cell signaling and homeostasis was established, and regulation of this pathway by PDE inhibitors arose as a field of considerable interest. (beds.ac.uk)
Cyclic AMP (cAMP) and cyclic GMP (cGMP) are critical second messengers for the regulation of cardiac function. (worldcat.org)

We demonstrated that two receptor-type adenylyl cyclases (CyaA and CyaB) of M. xanthus act as osmosensors. (asm.org)
Activation of PKG results in the regulation of several downstream targets, including myosin phosphatase targeting subunit (MYPT), myosin light chain kinase (MLCK), regulator of G-protein signalling (RGS)2, RhoA, Rho kinase (ROCK), inositol 1,4,5-triphosphate receptor-associated PKG substrate (IRAG), phospholamban (PLB) and calcium-sensitive potassium channels (BK Ca ). PGC: particulate guanylyl cyclases. (ersjournals.com)

Importantly, pharmacologic and genetic means to increase cellular cAMP levels either by activating cAMP-inducing G-protein-coupled receptors (GPR3 or β 2 adrenergic receptor) or ADCY1, or by inhibiting cAMP-reducing guanine nucleotide-binding protein G(i) subunit α2, C-X-C motif chemokine receptor type 4, or cAMP phosphodiesterases, sensitized cancer cells to CADs. (aacrjournals.org)

The Haase team could show that they are fine tuning signaling by Toll-like receptor 4, promoting the secretion of pro-inflammatory cytokines, whereas they downregulate the production of type-1 interferons and nitric monoxide. (uni-potsdam.de)
In the brain, two types of high‐affinity receptors bind glucocorticoids, the type I, mineralocorticoid receptor and the type II, glucocorticoid receptor (GR). Both receptor types are expressed by many types of neurons. (deepdyve.com)
This collaborative study using computational molecular modeling and FRET-based assays for cAMP revealed the promiscuous nature of glucagon and GLP-1 receptor agonist and antagonist action at family B GPCRs. (upstate.edu)
This study reveals that the GLP-1 receptor agonist Exendin-4 can be conjugated to vitamin B12 so that its bioavailability favors a glucoregulatory effect at the pancreas rather than a C.N.S. mediated effect to induce nausea. (upstate.edu)
This study was a collaboration with the laboratory of Dr. Robert N. Cooney of the Department of Surgery at SUNY Upstate in which the Holz laboratory participated in the discovery that the a7 nicotinic acetylcholine receptor is a pentameric cation channel that mediates stimulatory effects of GTS-21 on enteroendocrine L-cell GLP-1 release. (upstate.edu)
Modeling Analysis of Inositol 1,4,5-Trisphosphate Receptor-Mediated Ca2+ Mobilization Under The Control Of Glucagon-Like Peptide-1 In Mouse Pancreatic Beta-Cells. (upstate.edu)
8-Phenyltheophylline, an adenosine receptor antagonist in mammals, slightly retards memory decay in the wild-type. (springer.com)
Prompted by significant changes in the expression of genes involved in Ca 2+ and cyclic AMP (cAMP) signaling pathways in CAD-resistant MCF7 breast cancer cells, we identified here an early lysosomal Ca 2+ release through P2X purinergic receptor 4 (P2RX4) and subsequent Ca 2+ - and adenylyl cyclase 1 (ADCY1)-dependent synthesis of cAMP as a signaling route mediating CAD-induced lysosomal membrane permeabilization and cell death. (aacrjournals.org)
Insulin receptor substrate-1 (IRS-1) (-/-) mice are lean with a reduced fat cell size and have insulin resistance due to a primary defect of insulin signaling. (elsevier.com)
however, published receptor binding data also support the potential L-type voltage- operated calcium channel (L-VOCC) blocking effect of drotaverine. (aspetjournals.org)
The phenotype was the opposite of that of the receptor-type adenylyl cyclase ( cyaA or cyaB ) mutant. (asm.org)
At 30 days, their brains were assayed by receptor autoradiography for αr - and α2 -adrenoceptor binding with 1 nM [3 H]prazosin and 1 nM [3 H]paraminoclonidine, respectively. (iospress.com)
The novel GLP-1/GIP dual receptor agonist DA3-CH is neuroprotective in the pilocarpine-induced epileptogenesis rat model. (annals.org)

Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a protein that is encoded by the FREQ gene in humans. (wikipedia.org)
Taking advantage of the large growth cone size of cultured primary neurons from pond snail Lymnaea stagnalis combined with dsRNA knockdown, we show that neuronal calcium sensor-1 (NCS-1) regulates neurite extension and branching, and activity-dependent Ca 2+ signals in growth cones. (biologists.org)

Although both SLC30A8 rs13266634 single nucleotide polymorphism and plasma zinc concentrations have been associated with impaired glucose regulation (IGR) and type 2 diabetes (T2D), their interactions for IGR and T2D remain unclear. (diabetesjournals.org)
We selected and genotyped a PDE4D single nucleotide polymorphism (SNP 41, rs152312) as a candidate marker for susceptibility to ischemic stroke because SNP 41 has shown the most significant association with stroke in both a meta-analysis and the original Icelandic study of the PDE4D gene. (bvsalud.org)

The overall aim is to measure zinc signals and understand their function in the respective signal transduction pathways, and they were even able to identify molecular targets for zinc signals, such as cyclic nucleotide phosphodiesterases and protein tyrosine phosphatases. (uni-potsdam.de)
We suggest that cAMP phosphodiesterases have species-specific differential roles, which make them attractive antifungal targets, for combinatorial treatment. (elsevier.com)
cGMP targets cyclic nucleotide-dependent ion channels, phosphodiesterases, and 2 PKG isoforms (gene names and KRT13 antibody OB-KO). (fryda.org)

This includes a few exogenous, vertically transmitted and endogenous viruses of mice (type B) and some primate and sheep viruses (type D). MAMMARY TUMOR VIRUS, MOUSE is the type species. (bioportfolio.com)
Elevated fasting plasma glucagon levels ( 1 ) and reduced suppression of glucagon secretion after hyperglycemia ( 2 , 3 ) occurs in NOD mice and in spontaneously diabetic KK mice. (diabetesjournals.org)
However, islets can regulate glucagon over a glucose concentration range that is not associated with changes in insulin or somatostatin ( 7 ), and prediabetic NOD and KK mice show elevated fasting and nonfasting plasma glucagon levels without changes in plasma insulin or blood glucose ( 1 - 3 , 8 ). (diabetesjournals.org)
Phosphodiesterase 4B in the cardiac L-type Ca²⁺ channel complex regulates Ca²⁺ current and protects against ventricular arrhythmias in mice. (nih.gov)
Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance. (semanticscholar.org)
To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (-/-) mice. (elsevier.com)
In IRS-1 (-/-) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. (elsevier.com)
Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (-/-) mice. (elsevier.com)
Because we previously observed reduced NO signaling in osteoblasts from mice with streptozotocin-induced type 1 diabetes (18), we used diabetic mice to test the hypothesis that reduced PKG signaling impairs bone regeneration after injury and that PKG activation may improve fracture repair. (fryda.org)
mRNA in the kidney, lung, and brain was comparable in wild-type and KO mice (Supplemental Physique 1C). (fryda.org)
However, megakaryocytes stained for PKG1 in the bone tissue marrow of OB-KO mice highly, serving being a positive control (Body 1B, M). Open up in another window Body 1 Decreased osteoblastic gene appearance and bone development prices in mice with osteoblast-specific deletion. (fryda.org)
Using immunoblotting and radioenzymatic assay we showed that total cardiac cAMP and cGMP PDE activity and specific PDE2 activity was strongly increased in PDE2 TG compared to wild type (WT) mice. (worldcat.org)
Sarcomere shortening, Ca2+ transients and the whole L-type Ca2+ current (ICa,L) were recorded in adult ventricular myocytes from WT and PDE2 TG mice and isoprenaline (ISO) was used to examine and compare the [beta]-adrenergic ([beta]-AR) response of these parameters. (worldcat.org)
Effect of phosphodiesterase (1B, 2A, 9A and 10A) inhibitors on central nervous system cyclic nucleotide levels of rats and mice. (annals.org)
Studies in knockout mice indicate that eNOS-derived NO is the principle mediator of endothelium-dependent vasodilation in the pulmonary circulation, but both eNOS and iNOS play a role in chronic modulation of basal tone 1 . (ersjournals.com)

Molecular cloning, genomic positioning, promoter identification, and characterization of the novel cyclic amp-specific phosphodiesterase PDE4A10" (PDF). (wikipedia.org)
A partial characterization of the cyclic nucleotide phosphodiesterases of Drosophila melanogaster. (springer.com)
Identification and characterization of DdPDE3, a cGMP-selective phosphodiesterase from Dictyostelium. (embl.de)
Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. (embl.de)

Cyclic Nucleotide Phosphodiesterases, Type 5" is a descriptor in the National Library of Medicine's controlled vocabulary thesaurus, MeSH (Medical Subject Headings) . (harvard.edu)

We describe the discovery of potent and orally bioavailable tetrahydropyridopyrimidine inhibitors of phosphodiesterase 10A by systematic optimization of a novel HTS lead. (semanticscholar.org)

The gut hormone glucagon like peptide-1 (GLP-1) has been shown to have important effects on maintaining the function and health of the insulin producing beta cells. (bioportfolio.com)
6. IBMX, Org 9935, siguazodan and rolipram (1 - 50 microM), but not zaprinast, each augmented glucose-induced insulin secretion in the presence of 16.7 mM but not 1 mM glucose. (strath.ac.uk)
7. These findings, in a clonal insulin secreting cell line, are consistent with an important role for PDE3B in regulating the pool of cyclic AMP relevant to the modulation of glucose-induced insulin secretion. (strath.ac.uk)
It concerns a novel conjugation chemistry that is tailored to direct a GLP-1 analog to the peripheral circulation to stimulate insulin secretion, but not to the central nervous system so that the side effects of nausea and vomiting are minimized. (upstate.edu)
Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets. (upstate.edu)
Type 1 diabetes (T1D) is caused by the immune system inappropriately attacking the cells in the pancreas that produce insulin, the hormone that controls blood sugar levels. (psychcentral.com)
Phosphodiesterase (PDE) 3B, a major isoform of PDE in adipocytes, mediates the antilipolytic action of insulin. (elsevier.com)
Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. (elsevier.com)
Using sub-cellular fractionation, confocal microscopy and transmission electron microscopy of isolated mouse islets and INS-1 (832/13) cells, we show that endogenous and overexpressed PDE3B is localized to insulin granules and plasma membrane. (lu.se)

Gurban, A. Pharmacologic activity of phosphodiesterases and their inhibitors. (eurekaselect.com)

Inhibition of phosphodiesterase (PDE) 1 and 5 normalized SNPrelaxing effects in Ercc1 d/- to wild-type (WT) levels. (clinsci.org)

cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene. (wikipedia.org)
The 2,3-cyclic nucleotide 3-phosphodiesterase (CNPase) is a highly abundant membrane-associated enzyme in the myelin sheath of the vertebrate nervous system. (jove.com)
The enzyme is about twice as active in vitro in 1-10 mM Mn2+ than in the same concentration of Mg2+ or Ca2+. (embl.de)

However, there has been no study to examine if and how NCS-1 is involved in regulation of the window level of Ca 2+ permissive to neurite outgrowth. (biologists.org)
Metalloproteinase PAPP-A regulation of IGF-1 contributes to polycystic kidney disease pathogenesis. (mayo.edu)
Concerted regulation of focal adhesion dynamics by galectin-3 and tyrosine- phosphorylated caveolin‑1. (unistra.fr)

They are essential regulators of cyclic nucleotide signaling with diverse physiological functions. (axonmedchem.com)

Inhibition of sperm phosphodiesterase (PDE) has been shown to increase cAMP concentrations and stimulate motility and the acrosome reaction. (nih.gov)
cAMP can influence cell growth, differentiation, and movement as well as regulating specialized actions unique to specific cell types. (mcponline.org)
42 , 43 Cyclic-AMP (cAMP) downmodulates this positive signaling wave by suppressing SYK and PI3Kδ activity. (bloodjournal.org)
In the present study the roles of the two phosphodiesterases, as well as that of Gpa2, in agonist-induced cAMP signalling, growth, morphogenesis and response to some stresses have been investigated. (elsevier.com)
cAMP-phosphodiesterase in the synaptic regions of Drosophila brains. (springer.com)
The likelihood that these effects are mediated by cAMP via inhibition of a Ca 2+ -calmodulin-activated phosphodiesterase is discussed and related to other data. (illinois.edu)
To evaluate the time course of the cAMP changes in the different compartments, brief (15 seconds) pulses of isoprenaline (100 nmol/L) were applied to adult rat ventricular myocytes (ARVMs) while monitoring cAMP changes beneath the membrane using engineered cyclic nucleotide-gated channels and within the cytosol with the fluorescence resonance energy transfer-based sensor, Epac2-camps. (ahajournals.org)
cAMP kinetics in the two compartments were compared to the time course of the L-type Ca 2+ channel current ( I Ca,L ) amplitude. (ahajournals.org)
Indeed, the presence of subcellular compartments with different cAMP concentrations, also called cAMP microdomains, are inferred from L-type Ca 2+ channel current ( I Ca,L ) measurements in response to local β-AR stimulation in cardiomyocytes 5 and by direct monitoring of cAMP using fluorescence resonance energy transfer (FRET)-based sensors 6,7 or cyclic nucleotide-gated (CNG) channels. (ahajournals.org)
Morphological and pathogenicity defects in the cut2 mutant are fully restored with exogenous application of synthetic cutin monomers, cAMP, 3-isobutyl-1-methylxanthine, and diacylglycerol (DAG). (plantcell.org)
We also report that an M. xanthus CbpB containing two cyclic AMP (cAMP)-binding domains is involved in osmotic and temperature tolerance ( 11 ). (asm.org)
Campos and Zusman also observed that the formation of fruiting bodies was stimulated by the addition of cAMP to agar containing low levels of nutrients ( 1 ). (asm.org)
The degradation of cAMP is achieved by 3′,5′-cyclic nucleotide phosphodiesterases, which catalyze cleavage of 3′,5′-cAMP to 5′-cAMP. (asm.org)
They establish local cAMP pools by controlling the intensity, duration and compartmentalization of cyclic nucleotide-dependent signaling. (mdpi.com)

www.who.int/gho/publications/world_health_statistics/ 2017/en/ (Accessed June 10, 2018). (eurekaselect.com)

Treatment of HIV-1 AD8-infected monocyte derived macrophages (MDMs) with cGMP agonists and cGMP antagonists caused respectively increased and decreased virus replication. (biomedcentral.com)
Compounds 1 ( ESI-05) , 14c ( HJC0338 ) and 20i , selected from each series, have exhibited no inhibition of EPAC1-mediated Rap1-GDP exchange activity at 25 µM, indicating that they are EPAC2-specific antagonists. (pubmedcentralcanada.ca)

Biochemical data suggest the presence of at least one cGMP-specific phosphodiesterase (PDE) that is activated by cGMP. (embl.de)

Novel Mechanism for Cyclic Dinucleotide Degradation Revealed by Structural Studies of Vibrio Phosphodiesterase V-cGAP3. (harvard.edu)

2002 Nov 1;58(2):79-85. (elsevier.com)

Using the information achieved from the three CoMFA models, new structures have been designed in silico and their inhibitory activity on phosphodiesterase 7 was predicted. (nih.gov)

Molecular cloning of a novel splice variant of human type IVA (PDE-IVA) cyclic AMP phosphodiesterase and localization of the gene to the p13.2-q12 region of human chromosome 19 [corrected]" (PDF). (wikipedia.org)
The three members of this family are referred to as type 1A, type 1B, and type 1C and are each product of a distinct gene. (bvsalud.org)
Recently published studies from different populations provide apparently conflicting evidence on the association between the phosphodiesterase 4D (PDE4D) gene and ischemic stroke. (bvsalud.org)
daf-11 and daf-21 mutants have similar defects in several of these responses (reviewed in R iddle and A lbert 1997 ), suggesting that the daf-11 and daf-21 gene products (DAF-11 and DAF-21) act at the same step to regulate chemosensory transduction in several types of sensory neurons. (genetics.org)

Furthermore, other experiments are needed to shed more light on the role of NCS-1 and other mechanisms linked to signaling pathways related to inhibitory avoidance task. (labome.org)
These "upstream" events culminate in the activation of downstream, prosurvival, signaling pathways, including among others NF-κB, MAPK, and the AKT/mTOR complex 1 (mTORC1). (bloodjournal.org)

Vandecasteele, G. Cyclic nucleotide phosphodiesterases in heart and vessels: A therapeutic perspective. (eurekaselect.com)
2] Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. (axonmedchem.com)

Overall, the data showed that the induction of PAI-1 synthesis by endotoxin in vivo can be up- and down-regulated pharmacologically, but the mechanisms involved remain elusive. (tudelft.nl)
Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis. (semanticscholar.org)

Origin of Exopolyphosphatase Processivity: Fusion of an ASKHA Phosphotransferase and a Cyclic Nucleotide Phosphodiesterase Homolog. (purdue.edu)

Organisms1

Chemicals and Drugs48

Analytical, Diagnostic and Therapeutic Techniques and Equipment1

Phenomena and Processes12

Information Science3

Involvement of phosphodiesterase-cGMP-PKG pathway in intracellular Ca2+ oscillations in pituitary GH3 cells. (1/146)

Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. (2/146)

The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. (3/146)

Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11. (4/146)

Differential inhibition of multiple cAMP phosphodiesterase isozymes by isoflavones and tyrphostins. (5/146)

Differential changes in the expression of cyclic nucleotide phosphodiesterase isoforms in rat brains by chronic treatment with electroconvulsive shock. (6/146)

"cAMP-specific" phosphodiesterase contributes to cGMP degradation in cerebellar cells exposed to nitric oxide. (7/146)

Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. (8/146)

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Cyclic Nucleotide Phosphodiesterases, Type 1

3',5'-Cyclic-AMP Phosphodiesterases

Cyclic Nucleotide Phosphodiesterases, Type 4

Cyclic Nucleotide Phosphodiesterases, Type 3

Cyclic Nucleotide Phosphodiesterases, Type 2

Phosphoric Diester Hydrolases

2',3'-Cyclic-Nucleotide Phosphodiesterases

Nucleotides, Cyclic

Phosphodiesterase Inhibitors

3',5'-Cyclic-GMP Phosphodiesterases

Cyclic Nucleotide Phosphodiesterases, Type 5

Cyclic GMP

Cyclic Nucleotide Phosphodiesterases, Type 7

Cyclic AMP

Rolipram

1-Methyl-3-isobutylxanthine

Purinones

Isoenzymes

Molecular Sequence Data

Calmodulin

Amino Acid Sequence

Kinetics

Cyclic Nucleotide Phosphodiesterases, Type 6

Nucleotides

Phosphodiesterase 3 Inhibitors

Phosphodiesterase 4 Inhibitors

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone

Dibutyryl Cyclic GMP

Theophylline

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Cyclic Nucleotide-Gated Cation Channels

Phosphorus-Oxygen Lyases

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Cyclic GMP-Dependent Protein Kinases

Adenylate Cyclase

Second Messenger Systems

Papaverine

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8-Bromo Cyclic Adenosine Monophosphate

Calcium

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Cattle

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Isoproterenol

Xanthines

Binding Sites

Catalytic Domain

Signal Transduction

Vinca Alkaloids

Cyclic P-Oxides

Enzyme Activation

Substrate Specificity

Sequence Homology, Amino Acid

Involvement of phosphodiesterase-cGMP-PKG pathway in intracellular Ca2+ oscillations in pituitary GH3 cells. (1/146)

Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L-type Ca2+ current in rat ventricular myocytes. (2/146)

The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. (3/146)

Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11. (4/146)

Differential inhibition of multiple cAMP phosphodiesterase isozymes by isoflavones and tyrphostins. (5/146)

Differential changes in the expression of cyclic nucleotide phosphodiesterase isoforms in rat brains by chronic treatment with electroconvulsive shock. (6/146)

"cAMP-specific" phosphodiesterase contributes to cGMP degradation in cerebellar cells exposed to nitric oxide. (7/146)

Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. (8/146)

Characterization of calmodulin-dependent cyclic nucleotide phosphodiesterase isoenzymes | Biochemical Journal

2020 Cyclic Nucleotide Phosphodiesterases (GRS) Seminar GRC

Cellular distribution of phosphodiesterase isoforms in rat cardiac tissue. | Circulation Research

JoVE Search Results: Cyclic Nucleotide Phosphodiesterases%2C Type 5

West anthony r cyclic nucleotide phosphodiesterases in the central nervous system from biology to dru - найти leaguechampions.ru

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Chen Yan, Ph.D. - University of Rochester Medical Center

Chen Yan, Ph.D. - University of Rochester Medical Center

Ca2+ stimulation of adenylyl cyclase generates dynamic oscillations in cyclic AMP | Journal of Cell Science