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)

Dispersed mouse pancreas acinar cells were prepared in which phosphatidylinositol had been labeled with myo[2-3H]inositol. During incubation with 0.3 microM cholecystokinin octapeptide (CCK-8) for 15 min, there was a loss of [3H]phosphatidylinositol radioactivity (23%) and a 3-fold gain in trichloroacetic acid-soluble radioactivity. Replacement of NaCl by up to 58 mM LiCl did not significantly affect the amount of CCK-8-stimulated [3H]phosphatidylinositol breakdown or the gain in acid-soluble radioactivity. However, in normal medium, the product of phosphatidylinositol breakdown was almost all inositol, whereas in Li+-containing medium, the product was almost all inositol 1-phosphate. Similar results were obtained with acetylcholine which, in the presence of Li+, gave a dose-responsive increase in inositol 1-phosphate over the concentration range of 0.1 to 10 microM. No increased accumulation of [3H]inositol diphosphate or [3H]inositol triphosphate was detected in stimulated cells. Time courses in the presence of Li+ indicated that the formation of inositol 1-phosphate preceded the formation of inositol. Addition of up to 50 mM myoinositol to the incubation medium showed no diluting effect on the amount of [3H]inositol 1-phosphate found. The accumulation of inositol 1-phosphate is presumably due to the known ability of Li+ to inhibit myoinositol 1-phosphatase. The results provide clear evidence that stimulated phosphatidylinositol breakdown involves a phospholipase C type of phosphodiesterase activity. 1.25 mM Li+ gave half-maximal inositol 1-phosphate accumulation. This is close to the range of plasma Li+ levels which is used therapeutically in psychiatric disorders. In unstimulated cells, [3H]inositol 1-phosphate accumulation in the presence of Li+ corresponded to a breakdown rate for [3H]phosphatidylinositol of 2 to 3%/h.
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PMID:Lithium-induced accumulation of inositol 1-phosphate during cholecystokinin octapeptide- and acetylcholine-stimulated phosphatidylinositol breakdown in dispersed mouse pancreas acinar cells. 632 67

The standard patch-clamp technique was employed on enzymatically digested acinar cells of submucosal glands isolated from feline trachea. ATP (-10(-3) M) evoked bidirectional current responses and an initial inward current at -80 mV (Cl- current) was followed by an outward current at 0 mV of membrane potential (K+ current). Isoproterenol (ISO) alone did not evoke any significant current responses. However, ISO augmented the ATP-induced inward and outward currents. A phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, mimicked the augmentation by ISO. [Ca2+]i of acinar cells in isolated gland was measured using a fluorescent dye, fura 2. ATP (-10(-3) M) induced an immediate increase in [Ca2+]i followed by a prolonged plateau, and Ca2+ removal resulted in an initial increase alone without the prolonged phase. ISO also augmented the ATP-evoked increases in [Ca2+]i mainly in the plateau phases. Mucus glycoprotein (MGP) secretion was estimated by measuring trichloroacetic acid-precipitable [3H]glycoconjugates from isolated glands. ATP (-10(-3) M) evoked significant MGP secretion and ISO enhanced the ATP-induced MGP secretion. In contrast, adenosine (-10(-3) M) produced no significant responses in current, MGP secretion, or [Ca2+]i. These findings suggest that 1) P2-receptor stimulation and the resultant [Ca2+]i rise induced both electrolyte and MGP secretions and 2) ATP-induced secretion is enhanced by an adenosine 3',5'-cyclic monophosphate intracellular concentration [cAMP]i-rise after beta-receptor stimulation in airway submucosal glands.
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PMID:Extracellular ATP regulation of feline tracheal submucosal gland secretion. 807 38

The observation of large systematic variations in the purine nucleotides in perfused rat hearts inexplicable by known metabolic transformations led us to propose the existence of some unknown major form of nucleotide. Radiolabelling studies located a rapidly metabolized TCA/methanol-insoluble species in heart, kidney and liver which selective digestion and chromatography allied to 31P-nmr and mass spectrometry suggested to be a tetraphosphate derivative of adenosine and phosphoglyceric acid of the form p3Gri1p[pp5'p3Gri1p]npp5'A, oligo-phosphoglyceroyl-ATP. Partial chemical synthesis has confirmed this basic structure. We have shown that substantial amounts of oPG-ATP are located in liver mitochondrial intermembrane space tightly bound to a specific 3' phosphodiesterase which releases the monomer p3Gri1ppp5'A. Here we show that oPG-ATP is remarkably stabilized by Mg2+ ions and describe the 300-fold purification of the stable substrate-free form of the 3' phosphodiesterase; it has an apparent M(r) = 165k with possibly up to 4 subunits of M(r) = 42.5k, 41.9k, 40.5k and 38.9k. The potential function of oPG-ATP is briefly discussed.
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PMID:The control of cellular adenine nucleotides: the discovery and metabolism of an oligomeric derivative of ATP and phosphoglyceric acid in mitochondrial intermembrane space. 839 36

We investigated the alterations of major fatty acid components in epidermis by natural aging and photoaging processes, and by acute ultraviolet (UV) irradiation in human skin. Interestingly, we found that 11,14,17-eicosatrienoic acid (ETA), which is one of the omega-3 polyunsaturated acids, was significantly increased in photoaged human epidermis in vivo and also in the acutely UV-irradiated human skin in vivo, while it was significantly decreased in intrinsically aged human epidermis. The increased ETA content in the epidermis of photoaged human skin and acute UV-irradiated human skin is associated with enhanced expression of human elongase 1 and calcium-independent phosphodiesterase A(2). We demonstrated that ETA inhibited matrix metalloproteinase (MMP)-1 expression after UV-irradiation, and that inhibition of ETA synthesis using EPTC and NA-TCA, which are elongase inhibitors, increased MMP-1 expression. Therefore, our results suggest that the UV increases the ETA levels, which may have a photoprotective effect in the human skin.
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PMID:Skin aging and photoaging alter fatty acids composition, including 11,14,17-eicosatrienoic acid, in the epidermis of human skin. 2051 27

Retinitis pigmentosa (RP) encompasses a diverse group of Mendelian disorders leading to progressive degeneration of rods and then cones. For reasons that remain unclear, diseased RP photoreceptors begin to deteriorate, eventually leading to cell death and, consequently, loss of vision. Here, we have hypothesized that RP associated with mutations in phosphodiesterase-6 (PDE6) provokes a metabolic aberration in rod cells that promotes the pathological consequences of elevated cGMP and Ca2+, which are induced by the Pde6 mutation. Inhibition of sirtuin 6 (SIRT6), a histone deacetylase repressor of glycolytic flux, reprogrammed rods into perpetual glycolysis, thereby driving the accumulation of biosynthetic intermediates, improving outer segment (OS) length, enhancing photoreceptor survival, and preserving vision. In mouse retinae lacking Sirt6, effectors of glycolytic flux were dramatically increased, leading to upregulation of key intermediates in glycolysis, TCA cycle, and glutaminolysis. Both transgenic and AAV2/8 gene therapy-mediated ablation of Sirt6 in rods provided electrophysiological and anatomic rescue of both rod and cone photoreceptors in a preclinical model of RP. Due to the extensive network of downstream effectors of Sirt6, this study motivates further research into the role that these pathways play in retinal degeneration. Because reprogramming metabolism by enhancing glycolysis is not gene specific, this strategy may be applicable to a wide range of neurodegenerative disorders.
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PMID:Reprogramming metabolism by targeting sirtuin 6 attenuates retinal degeneration. 2784 58


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