Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two subclasses of cyclic guanosine monophosphate (GMP)-specific phosphodiesterases were identified in vascular tissue from several beds. The activity of one subclass (phosphodiesterase IB) was stimulated severalfold by calmodulin and selectively inhibited by the phosphodiesterase inhibitor TCV-3B. The activity of the other subclass (phosphodiesterase IC) was not stimulated by calmodulin and was selectively inhibited by the phosphodiesterase inhibitor M&B 22,948. To assess the involvement of both subclasses in regulating cyclic GMP-dependent responses, the ability of TCV-3B and M&B 22,948 to potentiate the in vitro and in vivo responses to the endogenous guanylate cyclase stimulator atrial natriuretic factor (ANF) was evaluated. Both TCV-3B and M&B 22,948 relaxed isolated rabbit aortic and pulmonary artery rings and also potentiated the relaxant effect of ANF. In addition, both inhibitors produced small increases in urine flow and sodium excretion in anesthetized rats and potentiated the diuretic and natriuretic responses to exogenous ANF. M&B 22,948 (30 micrograms/kg/min) produced a threefold increase in the natriuretic response to simultaneously administered ANF, and TCV-3B (10 micrograms/kg/min) produced a twofold increase in the response to ANF. The results of the present experiments suggest that both the calmodulin-sensitive and calmodulin-insensitive subclasses of cyclic GMP-specific phosphodiesterase play a role in regulating the in vitro and in vivo response to ANF.
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PMID:Subclasses of cyclic GMP-specific phosphodiesterase and their role in regulating the effects of atrial natriuretic factor. 215 39

Cyclic nucleotide-dependent protein phosphorylation plays a central role in neuronal signal transduction. Neurotransmitter-elicited increases in cAMP/cGMP brought about by activation of adenylyl and guanylyl cyclases are downregulated by multiple phosphodiesterase (PDE) enzymes. In brain, the calmodulin (CaM)-dependent isozymes are the major degradative activities and represent a unique point of intersection between the cyclic nucleotide- and calcium (Ca2+)-mediated second messenger systems. Here we describe the distribution of the PDE1B1 (63 kDa) CaM-dependent PDE in mouse brain. An anti-peptide antiserum to this isoform immunoprecipitated approximately 30-40% of cytosolic PDE activity, whereas antiserum to PDE1A2 (61 kDa isoform) removed 60-70%, demonstrating that these isoforms are the major CaM-dependent PDEs in brain. Quantification of PDE1B1 immunoreactivity on immunoblots indicated that striatum contains 3-17-fold higher levels of PDE1B1 than other brain regions, with lowest immunoreactivity in cerebellum. In situ hybridization demonstrated high levels of PDE1B1 mRNA in the caudate-putamen, nucleus accumbens, and olfactory tubercle. Moderate mRNA levels were observed in dentate gyrus, cerebral cortex, medial thalamic nuclei, and brainstem, whereas negligible mRNA was detectable in the globus pallidus, islands of Calleja, substantia nigra, and ventral tegmental area. Immunocytochemistry confirmed that the majority of PDE1B1 protein was localized to the caudate-putamen, nucleus accumbens, and olfactory tubercle. Within the caudate-putamen, PDE1B1 immunoreactivity was ubiquitous, while PDE1A2 immunostaining was restricted to a minor subset of striatal neurons. The expression of PDE1B1 protein and mRNA correlate strongly with areas of the brain that are richest in dopaminergic innervation; indeed, there are strikingly similar distributions for PDE1B1 and D1 dopamine receptor mRNAs. Since D1 receptor binding activates adenylyl cyclase, and striatal neurons lack CaM-sensitive forms of cyclase, the high amount of this PDE implies an important physiological role for Ca(2+)-regulated attenuation of cAMP-dependent signaling pathways following dopaminergic stimulation.
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PMID:Expression of a calmodulin-dependent phosphodiesterase isoform (PDE1B1) correlates with brain regions having extensive dopaminergic innervation. 812 Jun 23

Cytosolic extracts from a human lymphoblastoid B-cell line, RPMI-8392, established from a patient with acute lymphocytic leukemia, contain two major forms of cyclic nucleotide phosphodiesterase (PDE): Ca2+-calmodulin dependent PDE (PDE1) and cAMP-specific PDE (PDE4). In contrast, normal quiescent human peripheral blood lymphocytes (HPBL) are devoid of PDE1 activity [Epstein, P. M., Moraski, S., Jr., and Hachisu, R. (1987) Biochem. J. 243, 533-539]. Using reverse transcription-polymerase chain reaction (RT-PCR), we show that the mRNA encoding the 63-kDa form of PDE1 (PDE1B1) is expressed in RPMI-8392 cells, but not in normal, resting HPBL. This mRNA is, however, induced in HPBL following mitogenic stimulation by phytohemagglutinin (PHA). Also using RT-PCR, the full open reading frame for human PDE1B1 cDNA was cloned from RPMI-8392 cells and it encodes a protein of 536 amino acids with 96% identity to bovine, rat, and mouse species. RT-PCR also identifies the presence of PDE1B1 in other human lymphoblastoid and leukemic cell lines of B- (RPMI-1788, Daudi) and T-(MOLT-4, NA, Jurkat) cell origin. Inhibition of PDE1 or PDE4 activity by selective inhibitors induced RPMI-8392 cells, as well as the other cell lines, to undergo apoptosis. Culture of RPMI-8392 cells with an 18-bp phosphorothioate antisense oligodeoxynucleotide, targeted against the translation initiation region of the RPMI-8392 mRNA, led to a specific reduction in the amount of PDE1B1 mRNA after 1 day, and its disappearance after 2 days, and induced apoptosis in these cells in a sequence specific manner. This suggests that PDEs, particularly PDE1B1, because its expression is selective, may be useful targets for inducing the death of leukemic cells.
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PMID:Inhibition of calmodulin-dependent phosphodiesterase induces apoptosis in human leukemic cells. 885 39

A cDNA selection technique has been used to isolate full-length human cDNAs of the phosphodiesterase 1 (PDE1) calcium calmodulin (CaM)-regulated phosphodiesterase gene family. We isolated cDNAs representing multiple splice variants of PDE1A, 1B and 1C from a variety of tissues. Included among these were two novel splice variants for PDE1A and 1B. The first, PDE1A5, encodes a 519-residue protein, which is different from PDE1A1 by the insertion of 14 residues, a divergent carboxy terminus and also differs from PDE1A3 through a divergent amino terminus. Our second novel splice variant represents the first occurrence of a splice variant of the PDE1B gene. PDE1B2 encodes a 516-residue protein and diverges from PDE1B1 by the replacement of the first 38 residues by an alternative 18, which is predicted to be functionally significant. Using the splice variant sequence differences to perform comparative Northern analysis, we have demonstrated that each variant has a differential tissue distribution.
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PMID:Isolation and differential tissue distribution of two human cDNAs encoding PDE1 splice variants. 1174 89