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)

A "partial" rodent model for schizophrenia has been used to characterize the regulation of hippocampal genes in response to amygdalar activation. At 96 h after the administration of picrotoxin into the basolateral nucleus, we have observed an increase in the expression of genes associated with 18 different monoamine (ie adrenergic alpha 1, alpha 2 and beta 2, serotonergic 5HT5b and 5HT6, dopamine D4 and muscarinic m1, m2 and m3) and peptide (CCK A and B, angiotensin 1A, mu and kappa opiate, FSH, TSH, LH, GNRH, and neuropeptide Y) G-protein coupled receptors (GPCRs). These latter receptors are associated with three different G protein signaling pathways (Gq, Gs, and Gi) in which significant changes in gene expression were also noted for adenylate cyclase (AC4), phosphodiesterase (PDE4D), protein kinase A (PKA), and protein kinase C (PKC). Quantitative RT-PCR was used to validate the results and demonstrated that there were predictable increases of three GPCRs selected for this analysis, including the dopamine D4, alpha 1b, and CCK-B receptors. Eight out of the nine monoamine receptors showing these changes have moderate to high affinity for the atypical antipsychotic, clozapine. Taken together, these results suggest that amygdalar activation may play a role in the pathophysiology and treatment of psychosis by regulating the activity of multiple GPCR and metabolic pathways in hippocampal cells.
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PMID:Acute amygdalar activation induces an upregulation of multiple monoamine G protein coupled pathways in rat hippocampus. 1517 Apr 62

Signals that elevate intracellular levels of cyclic adenosine monophosphate (cAMP) are among the factors that control lipopolysaccharide (LPS)-mediated inflammatory mediator production by macrophages. cAMP signaling is also involved in maintaining body functions that are commonly impaired in sepsis, including the endothelial cell barrier function and heart function. Several agents successfully used for sepsis intervention target cAMP signaling, and it was recently shown that liver and lung may be protected from inflammation injury by cAMP-elevating phosphodiesterase inhibitors. Here, we show that LPS attenuates adenylyl cyclase (AC) mRNA levels in liver, lung, heart, spleen and kidney in an animal model of endotoxemia, and in macrophages from liver and lung. In particular, AC5, AC6, AC7 and AC9 mRNA were reduced in most tissues examined and in tissue macrophages. In Kupffer cells, prostaglandin E2-mediated cAMP production was inhibited by LPS treatment. The reduction in AC mRNA by LPS would be expected to lead to a lowered potential for cAMP production in most organs, and in particular, changes in AC6 mRNA may affect endothelial cell barrier function and heart function. In contrast, AC4 mRNA was elevated in heart and lung. The present work indicates a possible mechanism for LPS-mediated alteration of cAMP signaling in vivo.
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PMID:Lipopolysaccharide attenuates mRNA levels of several adenylyl cyclase isoforms in vivo. 1700 68

Receptor-mediated changes in cAMP production play an essential role in sympathetic and parasympathetic regulation of the electrical, mechanical, and metabolic activity of cardiac myocytes. However, responses to receptor activation cannot be easily ascribed to a uniform increase or decrease in cAMP activity throughout the entire cell. In this study, we used a computational approach to test the hypothesis that in cardiac ventricular myocytes the effects of beta(1)-adrenergic receptor (beta(1)AR) and M(2) muscarinic receptor (M(2)R) activation involve compartmentation of cAMP. A model consisting of two submembrane (caveolar and extracaveolar) microdomains and one bulk cytosolic domain was created using published information on the location of beta(1)ARs and M(2)Rs, as well as the location of stimulatory (G(s)) and inhibitory (G(i)) G-proteins, adenylyl cyclase isoforms inhibited (AC5/6) and stimulated (AC4/7) by G(i), and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that: 1), bulk basal cAMP can be high ( approximately 1 microM) and only modestly stimulated by beta(1)AR activation ( approximately 2 microM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A ( approximately 100 nM to approximately 2 microM); 2), M(2)R activation strongly reduces the beta(1)AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and 3), during weak beta(1)AR stimulation, M(2)R activation not only reduces caveolar cAMP, but also produces a rebound increase in caveolar cAMP following termination of M(2)R activity. We conclude that compartmentation of cAMP can provide a quantitative explanation for several aspects of cardiac signaling.
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PMID:Compartmentation of cAMP signaling in cardiac myocytes: a computational study. 1729 6