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General Comment |
Soderling SH, et al 1998 reported the
cloning and characterization of a cAMP-specific cyclic nucleotide
phosphodiesterase, PDE8.
Cyclic nucleotide phosphodiesterases (PDEs) regulate intracellular levels of cAMP
and cGMP by hydrolyzing them to their corresponding 5' monophosphates. The authors report
the cloning and characterization of a novel cAMP-specific PDE from mouse
testis. This unique phosphodiesterase contains a catalytic domain that overall shares
<40% sequence identity to the catalytic domain of all other known PDEs. Based on
this limited homology, this new PDE clearly represents a previously unknown PDE
gene family designated as PDE8. The cDNA for PDE8 is 3,678 nucleotides in length
and is predicted to encode an 823 amino acid enzyme. The cDNA includes a full ORF
as it contains an in-frame stop codon before the start methionine. PDE8 is specific for
the hydrolysis of cAMP and has a Km of 0.15 microM. Most common PDE inhibitors
are ineffective antagonists of PDE8, including the nonspecific PDE inhibitor
3-isobutyl-1-methylxanthine. Dipyridamole, however, an inhibitor that is generally
considered to be relatively specific for the cGMP selective PDEs, does inhibit PDE8
with an IC50 of 4.5 microM. Tissue distribution studies of 22 different mouse tissues
indicates that PDE8 has highest expression in testis, followed by eye, liver, skeletal
muscle, heart, 7-day embryo, kidney, ovary, and brain in decreasing order.
NCBI Summary:
Cyclic nucleotide phosphodiesterases (PDEs) catalyze hydrolysis of the 5-prime,3-prime-cyclic nucleotides cAMP and cGMP to the corresponding nucleoside 5-prime-monophosphates. Mammalian PDEs have been grouped into several families based on substrate affinities, inhibitor sensitivities, mode of regulation, and amino acid sequence homologies. The PDE8 family contains high-affinity cAMP-specific, IBMX (3-isobutyl-1-methyl-xanthine)-insensitive PDEs, such as PDE8B. All PDEs share a conserved C-terminal catalytic region and a variable N-terminal domain that presumably accounts for the distinctive regulatory properties unique to the individual families.[supplied by OMIM]
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Comment |
Characterization of Novel Phosphodiesterases in the Bovine Ovarian Follicle. Sasseville M et al. The phosphodiesterase (PDE) family is a group of enzymes that catalyses the transformation of cyclic nucleotides into 5'nucleotides. Based on rodents, the current mammalian model of PDE distribution in the ovarian follicle predicts Pde3a in the oocyte and Pde4d in the somatic cells. Using bovine as an experimental model, the present results showed that PDE3 was the predominant PDE activity in oocytes. However, cumulus cell cAMP-PDE activity was predominantly resistant to inhibition by 3-isobutyl-methylxantine (IBMX) indicating PDE8 activity (60% of total PDE activity) and a minor role for PDE4 (<5%). 20% of total oocyte PDE activity was also attributed to PDE8. PDE activity measurements in mural granulosa cells from 2 to 6 mm diameter suggest the presence of PDE4 and PDE8. In granulosa cells from follicles >10 mm, total PDE andPDE8 activities along with PDE8A protein level were increased compared to smaller follicles. RT-PCR experiments showed that cumulus cells expressed PDE8A, PDE8B and PDE10A. Western blot experiments showed PDE8A, PDE8B and PDE4D proteins in mural granulosa cells and cumulus-oocyte complexes. PDE8 inhibition using dipyridamole dose-dependently increased cAMP levels in the COC and delayed oocyte nuclear maturation. These results are the first to demonstrate the functional presence of PDE8 in the mammalian ovarian follicle. This challenges the recently described cell specific expression of cAMP-PDEs in the ovarian follicle and the notion that PDE4 is the predominant granulosa/cumulus cell PDE. These findings have implications for our understanding of hormonal regulation of folliculogenesis and the potential application of PDE inhibitors as novel contraceptives.
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