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Nitric oxide modulates bacterial biofilm formation through a multicomponent cyclic-di-GMP signaling network.
Plate L, Marletta MA
(2012) Mol Cell 46: 449-60
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Amino Acid Sequence, Bacterial Proteins, Biofilms, Cyclic GMP, Gammaproteobacteria, Guanylate Cyclase, Histidine Kinase, Models, Biological, Molecular Sequence Data, Nitric Oxide, Phosphorylation, Protein Kinases, Protein Structure, Tertiary, Receptors, Cytoplasmic and Nuclear, Second Messenger Systems, Sequence Homology, Amino Acid, Shewanella, Signal Transduction, Soluble Guanylyl Cyclase
Show Abstract · Added March 3, 2020
Nitric oxide (NO) signaling in vertebrates is well characterized and involves the heme-nitric oxide/oxygen-binding (H-NOX) domain of soluble guanylate cyclase as a selective NO sensor. In contrast, little is known about the biological role or signaling output of bacterial H-NOX proteins. Here, we describe a molecular pathway for H-NOX signaling in Shewanella oneidensis. NO stimulates biofilm formation by controlling the levels of the bacterial secondary messenger cyclic diguanosine monophosphate (c-di-GMP). Phosphotransfer profiling was used to map the connectivity of a multicomponent signaling network that involves integration from two histidine kinases and branching to three response regulators. A feed-forward loop between response regulators with phosphodiesterase domains and phosphorylation-mediated activation intricately regulated c-di-GMP levels. Phenotypic characterization established a link between NO signaling and biofilm formation. Cellular adhesion may provide a protection mechanism for bacteria against reactive and damaging NO. These results are broadly applicable to H-NOX-mediated NO signaling in bacteria.
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon.
Friedman EA, Harris PA, Wood AJ, Stein CM, Kurnik D
(2007) Clin Pharmacol Ther 81: 503-9
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Adult, Carbolines, Cold Temperature, Cross-Over Studies, Cyclic Nucleotide Phosphodiesterases, Type 5, Double-Blind Method, Female, Humans, Male, Phosphodiesterase Inhibitors, Raynaud Disease, Regional Blood Flow, Skin, Skin Temperature, Tadalafil, Vasoconstriction
Show Abstract · Added December 10, 2013
Raynaud's phenomenon (RP) is a disorder characterized by episodic periods of vasoconstriction typically provoked by exposure to cold. Phosphodiesterase 5 (PDE5) inhibitors may improve digital blood flow and clinical symptoms in patients with RP, but the mechanisms are unknown. We examined the hypothesis that a PDE5 inhibitor, tadalafil, attenuates cold-induced vasoconstriction. Additionally, we examined whether tadalafil reduced vascular dysfunction following ischemia, thus altering the response to repeated cooling. We conducted a double-blind, placebo-controlled crossover study in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg). Digital blood flow (flux) was measured by laser Doppler flowmetry at rest and during two graduated local heat and cold exposure cycles. Temperature-response curves were evaluated by E(max) (maximal flux during heating), E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50% and 90% of E(max)-E(min), respectively). Tadalafil did not increase baseline flux (81.0+/-73.0 vs 91.3+/-114.0 arbitrary unit (AU), P=0.57), E(max) (280.0+/-107.6 vs 279.5+/-119.8 AU, P=0.94), ET(50) (25.4+/-4.4 vs 26.6+/-5.7 degrees C, P=0.62), or ET(90) (21.2+/-3.9 vs 21.8+/-5.0 degrees C, P=0.78), (cycle 1 values presented). There were no differences between cycles on either study day. In conclusion, in patients with RP, single-dose tadalafil does not increase digital blood flow at baseline or in response to heating, nor does it attenuate cold-induced vasoconstriction. Furthermore, it does not precondition the endothelium to resist a second cooling challenge. The clinical benefit in patients with RP treated with PDE5 inhibitors probably involves mechanisms other than acute inhibition of cold-induced vasoconstriction.
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17 MeSH Terms
cGMP catabolism by phosphodiesterase 5A regulates cardiac adrenergic stimulation by NOS3-dependent mechanism.
Takimoto E, Champion HC, Belardi D, Moslehi J, Mongillo M, Mergia E, Montrose DC, Isoda T, Aufiero K, Zaccolo M, Dostmann WR, Smith CJ, Kass DA
(2005) Circ Res 96: 100-9
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Adenoviridae, Adrenergic beta-Agonists, Animals, Carbolines, Cyclic GMP, Cyclic GMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 5, Fluorescence Resonance Energy Transfer, Genetic Vectors, Guanylate Cyclase, Isoproterenol, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardial Contraction, NG-Nitroarginine Methyl Ester, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Phosphodiesterase Inhibitors, Piperazines, Purines, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta, Receptors, Cytoplasmic and Nuclear, Recombinant Fusion Proteins, Second Messenger Systems, Sildenafil Citrate, Soluble Guanylyl Cyclase, Sulfones, Tadalafil
Show Abstract · Added March 4, 2015
Beta-adrenergic agonists stimulate cardiac contractility and simultaneously blunt this response by coactivating NO synthase (NOS3) to enhance cGMP synthesis and activate protein kinase G (PKG-1). cGMP is also catabolically regulated by phosphodiesterase 5A (PDE5A). PDE5A inhibition by sildenafil (Viagra) increases cGMP and is used widely to treat erectile dysfunction; however, its role in the heart and its interaction with beta-adrenergic and NOS3/cGMP stimulation is largely unknown. In nontransgenic (control) murine in vivo hearts and isolated myocytes, PDE5A inhibition (sildenafil) minimally altered rest function. However, when the hearts or isolated myocytes were stimulated with isoproterenol, PDE5A inhibition was associated with a suppression of contractility that was coupled to elevated cGMP and increased PKG-1 activity. In contrast, NOS3-null hearts or controls with NOS inhibited by N(G)-nitro-L-arginine methyl ester, or soluble guanylate cyclase (sGC) inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one, showed no effect of PDE5A inhibition on beta-stimulated contractility or PKG-1 activation. This lack of response was not attributable to altered PDE5A gene or protein expression or in vitro PDE5A activity, but rather to an absence of sGC-generated cGMP specifically targeted to PDE5A catabolism and to a loss of PDE5A localization to z-bands. Re-expression of active NOS3 in NOS3-null hearts by adenoviral gene transfer restored PDE5A z-band localization and the antiadrenergic efficacy of PDE5A inhibition. These data support a novel regulatory role of PDE5A in hearts under adrenergic stimulation and highlight specific coupling of PDE5A catabolic regulation with NOS3-derived cGMP attributable to protein subcellular localization and targeted synthetic/catabolic coupling.
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34 MeSH Terms
Stimulation of serotonin transport by the cyclic GMP phosphodiesterase-5 inhibitor sildenafil.
Zhu CB, Hewlett WA, Francis SH, Corbin JD, Blakely RD
(2004) Eur J Pharmacol 504: 1-6
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Animals, CHO Cells, Cricetinae, Cyclic Nucleotide Phosphodiesterases, Type 5, Membrane Glycoproteins, Membrane Transport Proteins, Nerve Tissue Proteins, Phosphodiesterase Inhibitors, Piperazines, Protein Binding, Purines, Rats, Serotonin, Serotonin Plasma Membrane Transport Proteins, Sildenafil Citrate, Sulfones
Show Abstract · Added July 10, 2013
The serotonin (5-hydroxtryptamine, 5-HT) transporter (SERT) plays a critical role in the inactivation of synaptic 5-HT and has been implicated in multiple psychiatric and peripheral disorders. SERT regulation studies demonstrate that activation of cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-linked pathways can increase SERT activity. As cGMP actions are limited by cGMP-specific phosphodiesterase (PDEs), we investigated whether the cGMP-specific PDE5 inhibitor sildenafil (Viagra) can stimulate 5-HT uptake and potentiate cGMP-mediated regulation. In RBL-2H3 cells, SERT activity was stimulated by sildenafil in a concentration- and time-dependent manner. Sildenafil also enhanced the stimulation of SERT triggered by the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), effects blocked by the PKG inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8). Sildenafil stimulation of 5-HT uptake arises from an increase in 5-HT transport Vmax and is paralleled by elevated SERT surface antagonist binding, also H8-sensitive. These findings implicate cGMP-targeted PDEs in limiting the regulation of antidepressant-sensitive 5-HT transport.
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17 MeSH Terms
Evidence that additional mechanisms to cyclic GMP mediate the decrease in intracellular calcium and relaxation of rabbit aortic smooth muscle to nitric oxide.
Weisbrod RM, Griswold MC, Yaghoubi M, Komalavilas P, Lincoln TM, Cohen RA
(1998) Br J Pharmacol 125: 1695-707
MeSH Terms: 1-Methyl-3-isobutylxanthine, 3',5'-Cyclic-GMP Phosphodiesterases, Angiotensin II, Animals, Aorta, Calcium, Cyclic GMP, Dose-Response Relationship, Drug, Enzyme Inhibitors, Guanylate Cyclase, Manganese, Muscle Relaxation, Muscle, Smooth, Nitric Oxide, Oxadiazoles, Phosphodiesterase Inhibitors, Protein Kinase C, Purinones, Quinoxalines, Rabbits, Thionucleotides, Vasoconstrictor Agents, Vasodilator Agents
Show Abstract · Added March 11, 2015
1. The role of cyclic GMP in the ability of nitric oxide (NO) to decrease intracellular free calcium concentration [Ca2+]i and divalent cation influx was studied in rabbit aortic smooth muscle cells in primary culture. In cells stimulated with angiotensin II (AII, 10(-1) M), NO (10(-10) - 10(-6) M) increased cyclic GMP levels measured by radioimmunoassay and decreased [Ca2+]i and cation influx as indicated by fura-2 fluorimetry. 2. Zaprinast (10(-4) M), increased NO-stimulated levels of cyclic GMP by 3-20 fold. Although the phosphodiesterase inhibitor lowered the level of [Ca2+]i reached after administration of NO, the initial decreases in [Ca2+]i initiated by NO were not significantly different in magnitude or duration from those that occurred in the absence of zaprinast. 3. The guanylyl cyclase inhibitor, H-(1,2,4) oxadiazolo(4,3-a) quinoxallin-1-one (ODQ, 10(-5) M), blocked cyclic GMP accumulation and activation of protein kinase G, as measured by back phosphorylation of the inositol trisphosphate receptor. ODQ and Rp-8-Br-cyclic GMPS, a protein kinase G inhibitor, decreased the effects of NO, 10(-10) - 10(-8) M, but the decrease in [Ca2+]i or cation influx caused by higher concentrations of NO (10(-7) - 10(-6) M) were unaffected. Relaxation of intact rabbit aorta rings to NO (10(-7) - 10(-5) M) also persisted in the presence of ODQ without a significant increase in cyclic GMP. Rp-8-Br-cyclic GMPS blocked the decreases in cation influx caused by a cell permeable cyclic GMP analog, but ODQ and/or the protein kinase G inhibitor had no significant effect on the decrease caused by NO. 4. Although inhibitors of cyclic GMP, protein kinase G and phosphodiesterase can be shown to affect the decrease in [Ca2+]i and cation influx via protein kinase G, these studies indicate that when these mechanisms are blocked, cyclic GMP-independent mechanisms also contribute significantly to the decrease in [Ca2+]i and smooth muscle relaxation to NO.
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23 MeSH Terms
Activation of transducin guanosine triphosphatase by two proteins of the RGS family.
Nekrasova ER, Berman DM, Rustandi RR, Hamm HE, Gilman AG, Arshavsky VY
(1997) Biochemistry 36: 7638-43
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Cyclic Nucleotide Phosphodiesterases, Type 6, Enzyme Activation, GTP Phosphohydrolases, Phosphoproteins, Proteins, RGS Proteins, Rod Cell Outer Segment
Show Abstract · Added December 10, 2013
RGS proteins (regulators of G protein signaling) constitute a newly appreciated group of negative regulators of G protein signaling. Several members of this group stimulate the guanosine triphosphatase (GTPase) activity of various G protein alpha-subunits, including the photoreceptor G protein, transducin. In photoreceptor cells transducin GTPase is known to be substantially accelerated by the coordinated action of the gamma-subunit of its effector enzyme, cGMP phosphodiesterase (PDE gamma), and another yet unidentified membrane-associated protein factor. Here we test the possibility that this factor belongs to the RGS family of GTPase stimulators. We report a detailed kinetic analysis of transducin GTPase activation by two members of the RGS family, RGS4 and G alpha interacting protein (GAIP). RGS4, being at least 5-fold more potent than GAIP, stimulates the rate of transducin GTPase by 2 orders of magnitude. Neither RGS4 nor GAIP requires PDE gamma for activating transducin. Rather, PDE gamma causes a partial reversal of transducin GTPase activation by RGS proteins. The effect of PDE gamma is based on a decreased apparent affinity of RGS for the alpha-subunit of transducin. Our observations indicate that GTPase activity of transducin can be activated by at least two distinct mechanisms, one based on the action of RGS proteins alone and another involving the cooperative action of the effector enzyme and another protein.
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8 MeSH Terms
Arrestin with a single amino acid substitution quenches light-activated rhodopsin in a phosphorylation-independent fashion.
Gray-Keller MP, Detwiler PB, Benovic JL, Gurevich VV
(1997) Biochemistry 36: 7058-63
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Animals, Arginine, Arrestin, Binding Sites, Cattle, Enzyme Activation, Glutamic Acid, Light, Mutagenesis, Site-Directed, Phosphorylation, Rhodopsin
Show Abstract · Added December 10, 2013
Arrestins are members of a superfamily of regulatory proteins that participate in the termination of G protein-mediated signal transduction. In the phototransduction cascade of vertebrate rods, which serves as a prototypical G protein-mediated signaling pathway, the binding of visual arrestin is stimulated by phosphorylation of the C-terminus of photoactivated rhodopsin (Rh*). Arrestin is very selective toward light-activated phosphorhodopsin (P-Rh*). Previously we reported that a single amino acid substitution in arrestin, Arg175Gln, results in a dramatic increase in arrestin binding to Rh* [Gurevich, V. V., & Benovic, J. L. (1995) J. Biol. Chem. 270, 6010-6016]. Here we demonstrate that a similar mutant, arrestin(R175E), binds to light-activated rhodopsin independent of phosphorylation. Arrestin(R175E) binds with high affinity not only to P-Rh* and Rh* but also to light-activated truncated rhodopsin in which the C-terminus phosphorylation sites have been proteolytically removed. In an in vitro assay that monitored rhodopsin-dependent activation of cGMP phosphodiesterase (PDE), wild type arrestin quenched PDE response only when ATP was present to support rhodopsin phosphorylation. In contrast, as little as 30 nM arrestin(R175E) effectively quenched PDE activation in the absence of ATP. Arrestin(R175E) had no effect when the lifetime of Rh* no longer contributed to the time course of PDE activity, suggesting that it disrupts signal transduction at the level of rhodopsin-transducin interaction.
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12 MeSH Terms
Subunit structure of rod cGMP-phosphodiesterase.
Artemyev NO, Surendran R, Lee JC, Hamm HE
(1996) J Biol Chem 271: 25382-8
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Animals, Antibodies, Antibody Specificity, Blotting, Western, Cattle, Cell Membrane, Cross-Linking Reagents, Electrophoresis, Polyacrylamide Gel, Macromolecular Substances, Mice, Mice, Mutant Strains, Molecular Weight, Rod Cell Outer Segment, Succinimides, Ultracentrifugation
Show Abstract · Added December 10, 2013
The rod cGMP phosphodiesterase (PDE) is the G-protein-activated effector enzyme that regulates the level of cGMP in vertebrate photoreceptor cells. Rod cGMP PDE is generally viewed as a heterotrimeric protein composed of catalytic alpha and beta subunits ( approximately90 kDa each) and two copies of the inhibitory subunit gamma ( approximately 10 kDa). However, the possibility that rod PDE could exist as distinct isoforms, such as alphaalphagamma2 and betabetagamma2 has not been ruled out. We have studied this question using cross-linking of PDE subunits with maleimidobenzoyl-N-hydroxysuccinimide ester and para-phenyldimaleimide. The cross-linking resulted in major products with molecular mass of 100 and 150 kDa, a doublet at approximately 180-190 kDa, and a doublet at approximately 210-220 kDa. Cross-linked products were analyzed using polyclonal-specific anti-PDEalphabeta, anti-PDEalpha, anti-PDEbeta, or anti-PDEgamma antibodies. The anti-PDEalpha and anti-PDEalphabeta antibodies recognized all the cross-linked products, whereas anti-PDEbeta and anti-PDEgamma antibodies did not interact with the 150-kDa band, indicating that the composition of this band is most likely alphaalpha. Similar analysis of cross-linked products of trypsin-treated PDE preparations revealed bands that are likely formed by PDEbeta subunit. The molecular size of holo-PDE and trypsin-activated PDE were studied using analytical ultracentrifugation in order to determine if oligomerization of PDE could account for the cross-linking of identical PDE subunits. The sedimentation analysis of both holo-PDE and ta-PDE revealed homogeneous samples with molecular masses of approximately220 and approximately150 kDa, respectively. These results indicate that PDE is likely a mixture of the major species alphabetagamma2, minor species alphaalphagamma2, and possibly betabetagamma2. Our data are consistent with the detection of low PDE activity in the rd mouse, which lacks any functional PDEbeta subunit.
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16 MeSH Terms
Elevation of cGMP with normal expression and activity of rod cGMP-PDE in photoreceptor degenerate labrador retrievers.
Kommonen B, Kylma T, Cohen RJ, Penn JS, Paulin L, Hurwitz M, Hurwitz RL
(1996) Ophthalmic Res 28: 19-28
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Animals, Blotting, Western, Cyclic GMP, Disease Models, Animal, Dog Diseases, Dogs, Electroretinography, Enzyme Activation, Microscopy, Electron, Nerve Degeneration, Photoreceptor Cells, Reference Values, Retina, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Trypsin
Show Abstract · Added October 9, 2013
Cyclic guanosine 3',5'-monophosphate (cGMP) levels were determined in retinas from a strain of Labrador Retrievers with inherited retinal dystrophy manifesting at early stages of retinal differentiation. The cGMP contents of dystrophic retinas of dogs from 1 to 4 months of age (n = 7) were significantly higher (p = 0.001) than in age-matched controls of the same breed (n = 11). Ultrastructure along the vertical retinal meridian was studied in developing retinas and findings were related to those of age-matched wild-type controls of the same breed. Slow central to peripheral progression of degeneration was observed in affected dogs. No differences were found in total cGMP-phosphodiesterase (PDE) activity, in PDE subunit composition as determined by Western blotting of 2-month-old homozygote affected retinas, or in the amino acid sequence deduced from the nucleotide sequence of the PDE beta-subunit as compared to controls. This model of photoreceptor degeneration thus is the first case of an apparent abnormality of cGMP metabolism that is not associated with a defect in the PDE catalytic subunits, and it is also the first reported model not associated with severe developmental abnormalities and rapid degeneration.
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17 MeSH Terms
A site on transducin alpha-subunit of interaction with the polycationic region of cGMP phosphodiesterase inhibitory subunit.
Artemyev NO, Mills JS, Thornburg KR, Knapp DR, Schey KL, Hamm HE
(1993) J Biol Chem 268: 23611-5
MeSH Terms: 3',5'-Cyclic-GMP Phosphodiesterases, Amino Acid Sequence, Animals, Binding Sites, Cattle, Cross-Linking Reagents, Guanosine 5'-O-(3-Thiotriphosphate), Macromolecular Substances, Mass Spectrometry, Molecular Sequence Data, Peptides, Rod Cell Outer Segment, Transducin
Show Abstract · Added December 10, 2013
Activation of cGMP phosphodiesterase (PDE) by the rod G-protein transducin is a key event in visual signal transduction in vertebrate photoreceptor cells. Interaction between the GTP-bound form of the alpha-subunit of transducin (alpha t*) and the PDE inhibitory gamma-subunit (P gamma) is a major component of PDE activation. The central polycationic region of P gamma, P gamma-24-45, has been implicated as one of the sites involved in alpha t*.P gamma interaction. Here we determine the site on alpha t* that interacts with P gamma-24-45 using a photo-cross-linking approach. The synthetic peptides Cys(ACM)Tyr-P gamma-24-45-Cys (where ACM indicates acetamidomethyl group) and Cys-P gamma-24-45 were labeled with 4-(N-maleimido)benzophenone at the COOH and NH2 termini, respectively, and then cross-linked to alpha t. When the photoprobe was attached to the COOH terminus of the peptide, a specific high yield cross-linked product (80%) was formed between the peptide and alpha t GTP gamma S (guanosine 5'-O-(thiotriphosphate)). A lower yield of cross-linking (35%) was seen between the peptide and alpha t GDP. The site of cross-linking between Cys(ACM)Tyr-P gamma-24-45-Cys and alpha t GTP gamma S was localized to within alpha t-306-310 using a variety of chemical and proteolytic cleavages of the cross-linked product, analysis of the fragments with SDS-polyacrylamide gel electrophoresis, and matrix-assisted laser desorption ionization mass spectrometry.
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13 MeSH Terms