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

The mechanism of phosphaturia induced by cAMP infusion and the physiological role of extracellular cAMP in modulation of renal phosphate transport were examined. In cultured opossum kidney cells, extracellular cAMP (10-1,000 microM) inhibited Na-dependent phosphate uptake in a time- and concentration-dependent manner. The effect of cAMP was reproduced by ATP, AMP, and adenosine, and was blunted by phosphodiesterase inhibitors or by dipyridamole which inhibits adenosine uptake. [3H]cAMP was degraded extracellularly into AMP and adenosine, and radioactivity accumulated in the cells as labeled adenosine and, subsequently, as adenine nucleotides including cAMP. Radioactivity accumulation was decreased by dipyridamole and by inhibitors of phosphodiesterases and ecto-5'-nucleotidase, assessing the existence of stepwise hydrolysis of extracellular cAMP and intracellular processing of taken up adenosine. In vivo, dipyridamole abolished the phosphaturia induced by exogenous cAMP infusion in acutely parathyroidectomized (APTX) rats, decreased phosphate excretion in intact rats, and blunted phosphaturia induced by PTH infusion in APTX rats. These results indicate that luminal degradation of cAMP into adenosine, followed by cellular uptake of the nucleoside by tubular cells, is a key event which accounts for the phosphaturic effect of exogenous cAMP and for the part of the phosphaturic effect of PTH which is mediated by cAMP added to the tubular lumen under the influence of the hormone.
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PMID:Mechanisms whereby extracellular adenosine 3',5'-monophosphate inhibits phosphate transport in cultured opossum kidney cells and in rat kidney. Physiological implication. 132 99

Secondary hyperparathyroidism has been attributed to be responsible for the generalized aminoaciduria and phosphaturia of vitamin D deficiency. Since PTH acts in the kidney to generate cAMP, we explored the possibility that its synthetic analog, dbcAMP, would alter the renal transport of taurine (an amino acid lost in the urine in vitamin D deficiency) and Pi. Exposure of renal BBMV prepared from normal and vitamin D-calcium-deficient rats to dbcAMP at concentrations ranging between 10(-4) and 10(-7) M did not alter taurine uptake by these vesicles. Higher dbcAMP concentrations blunted uptake, but these concentrations reduced intravesicular volume, thus representing an artifact of osmolarity. Preincubation of BBMV with dbcAMP for times between 0 and 60 min at 0 or 25 degrees C also did not alter taurine accumulation. Hypotonic lysis of BBMV, allowing entry of the cyclic nucleotide, followed by isotonic resealing did not influence taurine uptake. The addition of potassium fluoride (to inhibit phosphodiesterase activity) and ATP (as an energy source) did not alter taurine accumulation at 60 sec. The uptake of Pi, which is influenced by PTH, was decreased by 25% following exposure to dbcAMP on the internal surface of the vesicle. These data indicate that the taurinuria observed in vitamin D deficiency is unlikely to be related to a PTH-induced increase in intracellular cAMP, unlike the changes in Pi transport, which is sensitive to cyclic nucleotides.
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PMID:Cyclic AMP does not alter taurine accumulation by rat renal brush border membrane vesicles. 255 56

We examined whether phosphonoformate (PFA) can cause phosphaturia through its direct action on brush-border membrane (BBM) in vivo. Infusion of PFA or of parathyroid hormone (PTH) to thyroparathyroidectomized rats caused a marked increase in fractional excretion of phosphate without changes in excretion of Na+ or of GFR. The PFA-induced phosphaturia was not accompanied by an increase in urinary adenosine-3',5'-cyclic monophosphate (cAMP); moreover, PFA added in vitro did not influence the PTH-sensitive adenylate cyclase and cAMP-phosphodiesterase in proximal convoluted tubules. In BBM vesicles (BBMV) from rats with PFA-elicited phosphaturia, neither the rate of Na+-Pi symport nor Na+-dependent binding of [14C]PFA on BBMV was changed, whereas in BBMV from PTH-infused rats the Vmax of Na+-Pi symport decreased. PFA is almost completely ultrafiltrable; no metabolic transformation of PFA was detected after [14C]PFA exposure to rat renal cortical slices, homogenate, or to blood. We conclude that PFA causes phosphaturia by direct inhibition of Na+-Pi symport across BBM in proximal tubules, acting from the luminal side. Thus PFA (foscarnet) has a unique direct mechanism of phosphaturic effect, via its action on Pi reabsorption in proximal tubules in vivo.
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PMID:Mechanism of phosphaturia elicited by administration of phosphonoformate in vivo. 284 55

Human disorders of phosphate (Pi) handling and hypophosphatemic rickets have been shown to result from mutations in PHEX, FGF23, and DMP1, presenting as X-linked recessive, autosomal-dominant, and autosomal-recessive patterns, respectively. We present the identification of an inactivating mutation in the ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene causing autosomal-recessive hypophosphatemic rickets (ARHR) with phosphaturia by positional cloning. ENPP1 generates inorganic pyrophosphate (PPi), an essential physiologic inhibitor of calcification, and previously described inactivating mutations in this gene were shown to cause aberrant ectopic calcification disorders, whereas no aberrant calcifications were present in our patients. Our surprising result suggests a different pathway involved in the generation of ARHR and possible additional functions for ENPP1.
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PMID:Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene. 2013 72