Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of N-methyl-D-aspartate (NMDA) receptors on neurons activates both cAMP and cGMP signaling pathways. Experiments were carried out to determine which phosphodiesterase (PDE) families are involved in the hydrolysis of the cyclic nucleotides formed via this mechanism, using primary neuronal cultures prepared from rat cerebral cortex and hippocampus. The nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) potentiated the ability of NMDA to increase cAMP and cGMP. However, among the family-selective inhibitors, only the PDE4 inhibitor rolipram enhanced the ability of NMDA to increase cAMP in the neurons. In contrast, only the PDE2 inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) enhanced the ability of NMDA to increase cGMP. Neither adenosine nor an adenosine deaminase inhibitor mimicked the effect of EHNA; this suggests that EHNA's inhibition of PDE2, not its effects on adenosine metabolism, mediates its effects on NMDA-stimulated cGMP concentrations. The PDE inhibitor-augmented effects of NMDA on cAMP and cGMP formation were antagonized by 5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate (MK-801), verifying NMDA receptor mediation. In contrast, only NMDA-mediated cGMP formation was affected by altering either nitric oxide signaling or guanylyl cyclase; this suggests that NMDA-induced changes in cAMP are not secondary to altered cGMP concentrations. Overall, the present findings indicate that cAMP and cGMP formed in neurons as a result of NMDA receptor stimulation are hydrolyzed by PDE4 and PDE2, respectively. Selective inhibitors of the two PDE families will differentially affect the functional consequences of activation of these two signaling pathways by NMDA receptor stimulation.
...
PMID:Hydrolysis of N-methyl-D-aspartate receptor-stimulated cAMP and cGMP by PDE4 and PDE2 phosphodiesterases in primary neuronal cultures of rat cerebral cortex and hippocampus. 1206 24

Treatment of cultured adult rat cardiac fibroblasts with interleukin-1beta (IL-1beta) induces the inducible nitric oxide synthase (iNOS) expression, increases nitric oxide (NO) and cGMP production, and attenuates cAMP accumulation in response to isoproterenol by ~50%. Reduced cAMP accumulation is due to NO production: the effect is mimicked by NO donors and prevented by N(G)-monomethyl-L-arginine, an NOS inhibitor. Effects of NO are not restricted to the beta-adrenergic response; the response to forskolin is similarly diminished. NO donors only slightly (12%) decrease forskolin-stimulated adenylyl cyclase (AC) activity in cardiac fibroblast plasma membranes, suggesting that the main effect of NO is not a direct one on AC. An inhibitor of soluble guanylyl cyclase inhibits the effects of IL-1beta and NO donors; inhibition of cGMP-dependent protein kinase is without effect. 3-Isobutyl-1-methylxanthine, a nonspecific phosphodiesterase (PDE) inhibitor, and erythro-9-(2-hydroxy-3-nonyl)adenine, a specific inhibitor of the cGMP-stimulated PDE (PDE2), completely restore cAMP accumulation in sodium nitroprusside-treated fibroblasts and largely reverse the attenuated response in IL-1beta-treated fibroblasts. Although NO reportedly acts by reducing AC activity in some cells, in cardiac fibroblasts NO production decreases cAMP accumulation largely by the cGMP-mediated activation of PDE2.
...
PMID:Attenuation of cAMP accumulation in adult rat cardiac fibroblasts by IL-1beta and NO: role of cGMP-stimulated PDE2. 1210 56

Developmental changes (from 2 to 26 weeks) in phosphodiesterase (PDE) activity in the rat submandibular gland were investigated. Major activities for both cAMP- and cGMP-PDE were present in the 100000 x g supernatant fractions (70-90% of total activities), but not in the pellet fractions, during development. The effects of stimulators (Ca(2+)/calmodulin and cGMP) and inhibitors (cGMP, cilostamide, rolipram and zaprinast) were investigated in the supernatant fractions. During development, PDE4 (cAMP-specific PDE) was a major PDE, indicating that the majority of cAMP is hydrolysed by PDE4. In the young rat, PDE1 hydrolysed cGMP three-fold more than the control, and PDE2 (cGMP-stimulated PDE) was present, indicating that the concentration of intracellular cGMP may be enhanced, and cGMP may function in the growth pathway in the submandibular gland. Chromatograms eluted on a Mono Q HR5/5 ion-exchange column supported the results of the inhibition studies: PDE1, PDE2, PDE3, PDE4 and PDE5 were present in the young submandibular gland, and PDE1, PDE3, PDE4 and PDE5 in the adult gland. Expression of PDE5 was detected by inhibition studies, reverse transcriptase-polymerase chain reaction and Western blotting in the submandibular gland.
...
PMID:Changes in phosphodiesterase activity in the developing rat submandibular gland. 1222 Oct 13

Cyclic nucleotide phosphodiesterases (PDEs) regulate all pathways that use cGMP or cAMP as a second messenger. Five of the 11 PDE families have regulatory segments containing GAF domains, 3 of which are known to bind cGMP. In PDE2 binding of cGMP to the GAF domain causes an activation of the catalytic activity by a mechanism that apparently is shared even in the adenylyl cyclase of Anabaena, an organism separated from mouse by 2 billion years of evolution. The 2.9-A crystal structure of the mouse PDE2A regulatory segment reported in this paper reveals that the GAF A domain functions as a dimerization locus. The GAF B domain shows a deeply buried cGMP displaying a new cGMP-binding motif and is the first atomic structure of a physiological cGMP receptor with bound cGMP. Moreover, this cGMP site is located well away from the region predicted by previous mutagenesis and structural genomic approaches.
...
PMID:The two GAF domains in phosphodiesterase 2A have distinct roles in dimerization and in cGMP binding. 1227 Nov 24

To understand changes in cyclic nucleotide metabolism in muscle disease states, the expression of phosphodiesterase (PDE) isozymes in normal mouse leg muscle was examined. Four subcellular fractions were generated by differential centrifugation at 10,000 x g and 100,000 x g. cAMP PDE activity was found predominately in the soluble fractions, while cGMP PDE activity was more evenly distributed amongst soluble and particulate fractions. Pharmacological inhibitors demonstrate that PDE4 represents the major cAMP hydrolyzing activity and PDE2 represents the major cGMP hydrolyzing activity in mouse leg muscle. PDE1 is expressed at low levels, while PDE3 and PDE5 are intermediate. Between 20 and 40% of total PDE activity remained in the presence of inhibitors for PDE1-PDE5, indicating that other PDE families contribute to the total PDE pool. Reverse-transcription PCR with family-specific primers showed expression of mRNA for PDE7-PDE9, supporting this conclusion. Total PDE activity was found to be elevated in tissue extracts from a mouse model of Duchenne's muscular dystrophy.
...
PMID:Cyclic nucleotide phosphodiesterase isozymes expressed in mouse skeletal muscle. 1256 38

The cyclic nucleotides perform a variety of roles in the formation and remodeling of the neuronal interaction. The membrane microdomain called "raft" has been paid much attention, for this domain contains many signal-transducing molecules including trimeric G proteins and cytoskeletal proteins. The raft domain is recovered in a low-density fraction after the treatment of the membrane with a non-ionic detergent such as Triton X-100. The enrichment of cholesterol and sphingolipids is ascribed to be responsible for the detergent insolubility. In this study we focused on the cyclic nucleotide signaling process in rafts prepared from the cerebral cortex of 10-day-old rat and the synaptic plasma membrane fraction and found the presence of a high cAMP and cGMP phosphodiesterase (PDE) activity. The activity was effectively inhibited with erythro-9-(2-hydroxy-3-nonyl)adenine, a PDE2-specific inhibitor but not with other inhibitors such as vinpocetine, quazione, or zaprinast. Further western blotting analysis confirmed the localization of PDE2 in the raft fraction. The presence of adenylyl cyclase V/VI and PKA in the raft fraction was also shown with Western blotting. These results suggest the participation of the raft in the cyclic nucleotide signaling cascade in neurons.
...
PMID:Localization of cyclic nucleotide phosphodiesterase 2 in the brain-derived Triton-insoluble low-density fraction (raft). 1257 60

Rhamnus nakaharai Hayata (Rhamnaceae), has been used as a folk medicine in Taiwan for treating constipation, inflammation, tumors and asthma. 3-O-methylquercetin (3-MQ), a main constituent of the plant, has been reported to inhibit total cAMP- and cGMP-phosphodiesterase (PDE) of guinea pig trachealis. Therefore we were interested in investigating the inhibitory effect of 3-MQ on various PDE isozymes from guinea pig lungs and hearts. Isolated guinea pig lungs and hearts were homogenized and centrifuged. The supernatant was chromatographed over a column of Q-sepharose, and eluted with various concentrations of NaCl. In the following order, PDE subtypes 1, 5, 2, 4 from lungs, and 3 from hearts were separated. The IC 50 values of 3-MQ on these isozymes were 31.9, 86.9, 18.6, 28.5 and 1.6 microM, respectively. 3-MQ (10-100 microM) non-competitively inhibited PDE2, but competitively inhibited PDE4. 3-MQ (1-10 microM) also competitively inhibited PDE3. However, 3-MQ (10-100 microM) did not competitively inhibit PDE1 and 5, although it had a tendency to competitively inhibit PDE1 at concentrations of 10 - 30 microM. The present results showed that K i value of 3-MQ was similar to that of milrinone in PDE3, and was not significantly different from that of Ro 20 - 1724 in PDE4, respectively. In conclusion, 3-MQ was revealed to be a selective and competitive PDE3/PDE4 inhibitor, although its inhibitory effect on PDE4 was not potent. Therefore, 3-MQ may have a potential in the treatment of asthma beside its antiviral activity.
...
PMID:3-O-methylquercetin more selectively inhibits phosphodiesterase subtype 3. 1270 96

The role of cyclic nucleotide phosphodiesterase (PDE) isoforms in the beta2-adrenergic stimulation of the L-type Ca2+ current (ICa,L) was investigated in frog ventricular myocytes using double patch-clamp and double-barrelled microperfusion techniques. Isoprenaline (ISO, 1 nM to 10 microM) was applied on one half of the cell, either alone or in the presence of PDE inhibitors, and the local and distant responses of ICa,L were used to determine the gradient of local vs. distant cAMP concentration (alpha). IBMX (100 microM), a non-selective PDE inhibitor, reduced alpha from 40 to 4.4 indicating a 9-fold reduction in intracellular cAMP compartmentation when all PDE activity was blocked. While PDE1 and PDE2 inhibition had no effect, PDE3 inhibition by milrinone (3 microM) or PDE4 inhibition by Ro 20-1724 (3 microM) reduced alpha by 6- and 4-fold, respectively. A simultaneous application of milrinone and Ro 20-1724 produced a similar effect to IBMX, showing that PDE3 and PDE4 were the major PDEs accounting for cAMP compartmentation. Okadaic acid (3 microM), a non-selective phosphatase inhibitor, or H89 (1 microM), an inhibitor of cAMP-dependent protein kinase (PKA), had no effect on the distant response of ICa,L to ISO indicating that PDE activation by PKA played a minor role in cAMP compartmentation. Our results demonstrate that PDE activity determines the degree of cAMP compartmentation in frog ventricular cells upon beta2-adrenergic stimulation. PDE3 and PDE4 subtypes play a major role in this process, and contribute equally to ensure a functional coupling of beta2-adrenergic receptors with nearby Ca2+ channels via local elevations of cAMP.
...
PMID:Role of cyclic nucleotide phosphodiesterase isoforms in cAMP compartmentation following beta2-adrenergic stimulation of ICa,L in frog ventricular myocytes. 1281 80

Although expression of natriuretic peptides in cardiac tissues is up-regulated in response to pressure overload, no significant change in cGMP level in hypertrophied ventricles was observed. Activities of two cyclic nucleotide phosphodiesterase (PDE) isoforms, Ca2+/calmodulin-stimulated PDE (PDE1) and cGMP-stimulated PDE (PDE2), were significantly higher in rat left ventricles 14 days after aortic banding. The absence of significant changes in PDE1A and PDE2A mRNA levels indicated that the two PDE activities were post-transcriptionally up-regulated. These results suggested that the increased cGMP-PDE activity in response to pressure overload plays an important role in neutralizing cGMP action in cardiac tissue.
...
PMID:cGMP-phosphodiesterase activity is up-regulated in response to pressure overload of rat ventricles. 1283 73

Migration and proliferation of endothelial cells in response to VEGF play an important role in angiogenesis associated to pathologies such as atherosclerosis, diabetes and tumor development. Elevation of cAMP in endothelial cells has been shown to inhibit growth factor-induced proliferation. Our hypothesis was that inactivation of cAMP-specific phosphodiesterases (PDEs) would inhibit angiogenesis. The purpose of this study was to evaluate the effect of PDE inhibitors on in vitro and in vivo angiogenesis, using human umbilical vein endothelial cell (HUVEC) and chick chorioallantoic membrane (CAM) models respectively. Here, we report that: 1) PDE2, PDE3, PDE4 and PDE5 are expressed in HUVEC; 2) EHNA (20 microM), PDE2 selective inhibitor, and RP73401 (10 microM), PDE4 selective inhibitor, are able to increase the intracellular cAMP level in HUVEC; 3) EHNA and RP73401 are able to inhibit proliferation, cell cycle progression and migration of HUVEC stimulated by VEGF; 4) these in vitro effects can be mimic by treating HUVEC with the cAMP analogue, 8-Br-cAMP (600 microM); 5) only the association of EHNA and RP73401 inhibits in vivo angiogenesis, indicating that both migration and proliferation must be inhibited. These data strongly suggest that PDE2 and PDE4 represent new potential therapeutic targets in pathological angiogenesis.
...
PMID:VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors. 1288 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---