PT  - JOURNAL ARTICLE
AU  - Georges Némoz
AU  - Claudio Sette
AU  - Marco Conti
TI  - Selective Activation of Rolipram-Sensitive, cAMP-Specific Phosphodiesterase Isoforms by Phosphatidic Acid
AID  - 10.1124/mol.51.2.242
DP  - 1997 Feb 01
TA  - Molecular Pharmacology
PG  - 242--249
VI  - 51
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/51/2/242.short
4100  - http://molpharm.aspetjournals.org/content/51/2/242.full
SO  - Mol Pharmacol1997 Feb 01; 51
AB  - 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, andPDE4D). 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 theV max value of PDE4D3 without affecting theK m 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.