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Unité 352 Institut National de la Santé et de la
Recherche Médicale, Biochimie et Pharmacologie Institut National
des Sciences Appliquées-Lyon, 69621 Villeurbanne, France (G.N.), and
Division of Reproductive Biology, Department of Gynecology and
Obstetrics, Stanford University School of Medicine, Stanford,
California 94305 (C.S., M.C.)
In rat thymic lymphocytes, accumulation of phosphatidic acid (PA)
occurs at the same time as decrease in cAMP levels and activation of a
cAMP-specific phosphodiesterase (PDE) [type 4, EC 3.1.4.17 (PDE4)].
We investigated the nature of the PDE activated by PA and the mechanism
of activation by using recombinant cAMP-specific PDE4 isoforms derived
from three different genes (PDE4A, PDE4B, and
PDE4D). The "long" variants expressed from each gene
(PDE4A5, PDE4B1, and PDE4D3) were activated by PA, whereas the
"short" variants (PDE4A1, PDE4B2, PDE4D1, and PDE4D2) were not.
Phosphatidylserine was an activator that was as effective as PA,
whereas phosphatidylcholine was ineffective, indicating that activation
was restricted to anionic phospholipids. PA caused an increase in the
Vmax value of PDE4D3 without affecting the
Km value of the enzyme for the
cAMP substrate. PA also caused a change in the Mg2+
requirement for hydrolysis. Half-maximal stimulation of the PDE was
obtained with ~10 µg/ml PA. Although protein kinase A-mediated phosphorylation of PDE4D3 produces effects similar to those elicited by
PA, the mechanism of PA-induced activation was not found to involve a
phosphorylation. Instead, several observations suggest that PA may
directly interact with the enzyme. The stimulation of cAMP PDEs by PA
and other acidic phospholipids may be a mechanism by which growth
factors and hormones modulate the cAMP-dependent signal transduction
pathway during cell stimulation.
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