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Nucleotide Phosphodiesterase (nucleotide + phosphodiesterase)
Kinds of Nucleotide Phosphodiesterase Selected AbstractsORIGINAL RESEARCH,BASIC SCIENCE: Immunohistochemical Description of Cyclic Nucleotide Phosphodiesterase (PDE) Isoenzymes in the Human Labia MinoraTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2007Stefan Ückert PhD ABSTRACT Introduction., Up until now, only minimal research has been carried out on those female genital organs known to contribute to the normal cycle of sexual arousal and orgasm. Some findings indicated that there might be a significance of cyclic nucleotide-mediated pathways in the control of the normal function of female genital tissues. Aim., To elucidate, by means of immunohistochemistry, the distribution of the phosphodiesterase (PDE) isoenzymes 1, 3, 4, 5, 10, and 11 in the human labia minora. Main Outcome Measures., The amount of immunohistochemical staining specific for cyclic adenosine monophosphate (cAMP)- and/or cyclic guanosine monophosphate (cGMP)-degrading PDE isoenzymes was detected. Methods., Human labial tissue was obtained from four female cadavers (age at death: 18,42 years). Vibratome sections prepared from formaldehyde-fixated tissue specimens were incubated with primary antibodies directed against the respective PDE isoenzymes. Sections were then incubated with fluorochrome (fluorescein isothiocyanate, Texas Red)-labeled secondary antibodies. Visualization was commenced by means of a laser fluorescence microscope. Results., Immunostaining indicating the expression of PDE4 and PDE5 was abundantly observed in the smooth musculature of vessels interspersing the tissue. Immunoreactions specific for PDE3 were recognized in epithelial and subepithelial layers, sebaceous glands, and interstitial or neuroendocrine-like single cells located in the epithelium. Signals related to PDE10 and PDE11 were limited to the epithelium or glandular-like structures, respectively. Conclusions., Our results, for the first time, demonstrate the presence of cAMP- and cGMP-PDE isoenzymes in the human labia minora and give a hint to a significance of PDE4 and PDE5 in the control of labial vascular tissue function. Ückert S, Oelke M, Albrecht K, Stief C, Jonas U, and Hedlund P. Immunohistochemical description of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human labia minora. J Sex Med 2007;4:602,608. [source] Identification of rat cyclic nucleotide phosphodiesterase 11A (PDE11A)FEBS JOURNAL, Issue 16 2001Comparison of rat, human PDE11A splicing variants ,We have isolated and characterized rat cyclic nucleotide phosphodiesterase (PDE)11A, which exhibits properties of a dual-substrate PDE, and its splice variants (RNPDE11A2, RNPDE11A3, and RNPDE11A4). The deduced amino-acid sequence of the longest form of rat PDE11A splice variant, RNPDE11A4, was 94% identical with that of the human variant (HSPDE11A4). Rat PDE11A splice variants were expressed in a tissue-specific manner. RNPDE11A4 showed unique tissue distribution distinct from HSPDE11A4, which is specifically expressed in the prostate. Rat PDE11A splice variants were expressed in COS-7 cells, and their enzymatic characteristics were compared. Although the Km values for cAMP and cGMP were similar for all of them (1.3,1.6 and 2.1,3.9 µm, respectively), the Vmax values differed significantly (RNPDE11A4 >> RNPDE11A2 > RNPDE11A3). Human PDE11A variants also displayed very similar Km values and significantly different Vmax values (HSPDE11A4 >> HSPDE11A2 > HSPDE11A3 >> HSPDE11A1). The Vmax values of HSPDE11A4 for cAMP and cGMP were at least 100 times higher than those of HSPDE11A1. These observations indicate unique characteristics of PDE11A splicing variants. [source] An abnormal gene expression of the ,-adrenergic system contributes to the pathogenesis of cardiomyopathy in cirrhotic rats,HEPATOLOGY, Issue 6 2008Giulio Ceolotto Decreased cardiac contractility and ,-adrenergic responsiveness have been observed in cirrhotic cardiomyopathy, but their molecular mechanisms remain unclear. To study ,-adrenergic,stimulated contractility and ,-adrenergic gene expression patterns, 20 Wistar Kyoto rats were treated with carbon tetrachloride to induce cirrhosis and 20 rats were used as controls. Left ventricular contractility was recorded in electrically driven isolated hearts perfused at constant flow with isoproterenol (10,10 to 10,6 M). A cardiac gene expression profile was obtained using a microarray for the myocyte adrenergic pathway. The cardiac contractility maximal response to isoproterenol was significantly reduced in cirrhotic rats in comparison to control rats, whereas the half-maximal effective concentration was not different. In cirrhotic rats, cardiac gene expression analysis showed a significant overexpression of G protein alpha,inhibiting subunit 2 (G,i2), cyclic nucleotide phosphodiesterase (PDE2a), regulator of G-protein signaling 2 (RGS2), and down-expression of adenylate cyclase (Adcy3). These results indicate that overexpression of G,i2, PDE2a, and RGS2 down-regulates the ,-adrenergic signaling pathway, thus contributing to the pathogenesis of cirrhotic cardiomyopathy. (HEPATOLOGY 2008;48:1913-1923.) [source] 2,,3,-Cyclic nucleotide 3,-phosphodiesterase: A novel RNA-binding protein that inhibits protein synthesisJOURNAL OF NEUROSCIENCE RESEARCH, Issue 5 2009Michel Gravel Abstract 2,,3,-Cyclic nucleotide 3,-phosphodiesterase (CNP) is one of the earliest myelin-related proteins to be specifically expressed in differentiating oligodendrocytes (ODCs) in the central nervous system (CNS) and is implicated in myelin biogenesis. CNP possesses an in vitro enzymatic activity, whose in vivo relevance remains to be defined, because substrates with 2,,3,-cyclic termini have not yet been identified. To characterize CNP function better, we previously determined the structure of the CNP catalytic domain by NMR. Interestingly, the structure is remarkably similar to the plant cyclic nucleotide phosphodiesterase (CPDase) from A. thaliana and the bacterial 2,-5, RNA ligase from T. thermophilus, which are known to play roles in RNA metabolism. Here we show that CNP is an RNA-binding protein. Furthermore, by using precipitation analyses, we demonstrate that CNP associates with poly(A)+ mRNAs in vivo and suppresses translation in vitro in a dose-dependent manner. With SELEX, we isolated RNA aptamers that can suppress the inhibitory effect of CNP on translation. We also demonstrate that CNP1 can bridge an association between tubulin and RNA. These results suggest that CNP1 may regulate expression of mRNAs in ODCs of the CNS. © 2008 Wiley-Liss, Inc. [source] Protein microarray analysis identifies cyclic nucleotide phosphodiesterase as an interactor of Nogo-ANEUROPATHOLOGY, Issue 1 2010Kenta Sumiyoshi Nogo-A, a neurite outgrowth inhibitor, is expressed exclusively on oligodendrocytes and neurons in the CNS. The central domain of Amino-Nogo spanning amino acids 567,748 in the human Nogo-A designated NIG, mediates persistent inhibition of axonal outgrowth and induces growth cone collapse by signaling through an as yet unidentified NIG receptor. We identified 82 NIG-interacting proteins by screening a high-density human protein microarray composed of 5000 proteins with a recombinant NIG protein as a probe. Following an intensive database search, we selected 12 neuron/oligodendrocyte-associated NIG interactors. Among them, we verified the molecular interaction of NIG with 2,, 3,-cyclic nucleotide 3,-phosphodiesterase (CNP), a cell type-specific marker of oligodendrocytes, by immunoprecipitation and cell imaging analysis. Although CNP located chiefly in the cytoplasm of oligodendrocytes might not serve as a cell-surface NIG receptor, it could act as a conformational stabilizer for the intrinsically unstructured large segment of Amino-Nogo. [source] ORIGINAL RESEARCH,BASIC SCIENCE: Immunohistochemical Description of Cyclic Nucleotide Phosphodiesterase (PDE) Isoenzymes in the Human Labia MinoraTHE JOURNAL OF SEXUAL MEDICINE, Issue 3 2007Stefan Ückert PhD ABSTRACT Introduction., Up until now, only minimal research has been carried out on those female genital organs known to contribute to the normal cycle of sexual arousal and orgasm. Some findings indicated that there might be a significance of cyclic nucleotide-mediated pathways in the control of the normal function of female genital tissues. Aim., To elucidate, by means of immunohistochemistry, the distribution of the phosphodiesterase (PDE) isoenzymes 1, 3, 4, 5, 10, and 11 in the human labia minora. Main Outcome Measures., The amount of immunohistochemical staining specific for cyclic adenosine monophosphate (cAMP)- and/or cyclic guanosine monophosphate (cGMP)-degrading PDE isoenzymes was detected. Methods., Human labial tissue was obtained from four female cadavers (age at death: 18,42 years). Vibratome sections prepared from formaldehyde-fixated tissue specimens were incubated with primary antibodies directed against the respective PDE isoenzymes. Sections were then incubated with fluorochrome (fluorescein isothiocyanate, Texas Red)-labeled secondary antibodies. Visualization was commenced by means of a laser fluorescence microscope. Results., Immunostaining indicating the expression of PDE4 and PDE5 was abundantly observed in the smooth musculature of vessels interspersing the tissue. Immunoreactions specific for PDE3 were recognized in epithelial and subepithelial layers, sebaceous glands, and interstitial or neuroendocrine-like single cells located in the epithelium. Signals related to PDE10 and PDE11 were limited to the epithelium or glandular-like structures, respectively. Conclusions., Our results, for the first time, demonstrate the presence of cAMP- and cGMP-PDE isoenzymes in the human labia minora and give a hint to a significance of PDE4 and PDE5 in the control of labial vascular tissue function. Ückert S, Oelke M, Albrecht K, Stief C, Jonas U, and Hedlund P. Immunohistochemical description of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human labia minora. J Sex Med 2007;4:602,608. [source] Ibudilast: A Non-selective PDE Inhibitor with Multiple Actions on Blood Cells and the Vascular WallCARDIOVASCULAR THERAPEUTICS, Issue 3 2001Yukio Kishi ABSTRACT Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is a nonselective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is widely used in Japan for improving prognosis and relieving symptoms in patients suffering from ischemic stroke or bronchial asthma. These clinical applications are based on the properties of ibudilast that inhibit platelet aggregation, improve cerebral blood flow and attenuate allergic reactions. The inhibition of platelet aggregation and vasodilatation by ibudilast may be due to synergistic elevation of intracellular cyclic nucleotides and release of nitric oxide (NO) or prostacyclin from endothelium, rather than direct inhibition of PDE5 or PDE3. Another important property of ibudilast is its antiinflammatory activity possibly associated with potent inhibition of PDE4. Combined with its relaxing effects on bronchial smooth muscle, antiinflammatory actvity of ibudilast could favorably influence pathophysiology of asthma by antagonizing chemical mediators triggering asthmatic attacks. Ibudilast was also reported to significantly attenuate inflammatory cell infiltration in the lumbar spinal cord in an animal model of encephalomyelitis. Future investigations should include effects of ibudilast on inflammatory reactions between endothelium and blood cells, which may initiate the development of atherosclerosis. [source] Adenylyl cyclase Rv0386 from Mycobacterium tuberculosis H37Rv uses a novel mode for substrate selectionFEBS JOURNAL, Issue 12 2005Lucila I. Castro Class III adenylyl cyclases usually possess six highly conserved catalytic residues. Deviations in these canonical amino acids are observed in several putative adenylyl cyclase genes as apparent in several bacterial genomes. This suggests that a variety of catalytic mechanisms may actually exist. The gene Rv0386 from Mycobacterium tuberculosis codes for an adenylyl cyclase catalytic domain fused to an AAA-ATPase and a helix-turn-helix DNA-binding domain. In Rv0386, the standard substrate, adenine-defining lysine-aspartate couple is replaced by glutamine-asparagine. The recombinant adenylyl cyclase domain was active with a Vmax of 8 nmol cAMP·mg,1·min,1. Unusual for adenylyl cyclases, Rv0386 displayed 20% guanylyl cyclase side-activity with GTP as a substrate. Mutation of the glutamine-asparagine pair either to alanine residues or to the canonical lysine-aspartate consensus abolished activity. This argues for a novel mechanism of substrate selection which depends on two noncanonical residues. Data from individual and coordinated point mutations suggest a model for purine definition based on an amide switch related to that previously identified in cyclic nucleotide phosphodiesterases. [source] ONIOM quantum chemistry study of cyclic nucleotide recognition in phosphodiesterase 5INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 12 2007Kerrie A. O'Brien Abstract Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that contribute to the regulation of cyclic nucleotides in the cell by catalyzing the hydrolysis reaction of the O3,-phosphorous bond, yielding the noncyclic nucleotide as the product. The principal substrates are cyclic 3,,5,-adenosine and -guanosine monophosphate (cAMP and cGMP). PDE5, an important target of drug inhibition, is known to be highly selective for hydrolysis of cGMP. We use all-quantum hybrid calculations to accurately describe the binding interactions between PDE5 and cAMP/cGMP for the first time. The main reasons for cGMP preference in PDE5 are found to be to the fixed orientation of a conserved glutamine residue (Gln 817) together with the fixed orientation of a nonconserved glutamine residue (Gln 775). We report ONIOM(B3LYP/6-31g(d):PM3MM) binding energies, which reflect favorable guanine alignment with Gln 817 and steric crowding of adenine by Gln 775. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [source] Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 2 2005Ana Castro Abstract The activity of phosphodiesterases (PDEs) is associated with a wide variety of diseases and an intense effort toward the development of specific PDEs inhibitors has been generated for the last years. They are the enzymes responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate, and their complexity, as well as their different functional role, makes these enzymes a very attractive therapeutic target. This review is focused on the role of PDEs played on immunomodulatory processes and the advance on the development of specific inhibitors, covering PDEs mainly related to the regulation of autoimmune processes, PDE4 and PDE7. The review also highlights the novel structural classes of PDE4 and PDE7 inhibitors, and the therapeutic potential that combined PDE4/PDE7 inhibitors offer as immunomodulatory agents. © 2004 Wiley Periodicals, Inc. Med Res Rev [source] | |||||||||||||