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Molecular Pharmacology

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Abstract

Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE-4D3.

R Alvarez, C Sette, D Yang, R M Eglen, R Wilhelm, E R Shelton and M Conti
Molecular Pharmacology October 1995, 48 (4) 616-622;
R Alvarez
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C Sette
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D Yang
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R M Eglen
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R Wilhelm
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E R Shelton
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M Conti
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Abstract

Prostaglandin E2 produces a transient increase in the intracellular concentration of cAMP in a human promonocytic cell line (U937). The temporal pattern consists of a rapid increase followed by a gradual decline to a new steady state. The decline phase coincides with an increase in the activity of a high affinity form of cAMP phosphodiesterase (PDE). Immunoprecipitation with specific antibodies revealed that the activated enzyme is a variant of PDE-4D. To confirm this observation, three isoforms of human PDE-4 (A, B, and D) were cloned and expressed in Sf9 cells with recombinant baculovirus infection. The activity of only one of the isoforms (PDE-4D3) increased after incubation with the catalytic subunit of protein kinase A and Mg-ATP. Hydrolytic activity of human PDE-4D3 was dependent on Mg2+. Before phosphorylation, the concentration-response curve for Mg2+ was biphasic and ranged from 0.1 to 100 mM. Phosphorylation of PDE-4D3 by protein kinase A produced a monophasic Mg2+ response curve (0.5 Vmax = 0.2 mM). Phosphorylation of PDE-4D3 increased the sensitivity of the enzyme to inhibition by RS-25344 (approximately 100-fold) and RS-33793 (approximately 330-fold). Thus, phosphorylation of PDE-4D3 induces an apparent conformation change that increases maximum velocity and sensitivity to inhibition by some analogues of nitraquazone. These observations provide the basis for a novel pharmacological strategy that targets an activated form of PDE in human leukocytes. Selective PDE-4D3 inhibitors may have useful anti-inflammatory properties with fewer adverse side effects than other PDE-4 inhibitors.

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Molecular Pharmacology
Vol. 48, Issue 4
1 Oct 1995
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Abstract

Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE-4D3.

R Alvarez, C Sette, D Yang, R M Eglen, R Wilhelm, E R Shelton and M Conti
Molecular Pharmacology October 1, 1995, 48 (4) 616-622;

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Abstract

Activation and selective inhibition of a cyclic AMP-specific phosphodiesterase, PDE-4D3.

R Alvarez, C Sette, D Yang, R M Eglen, R Wilhelm, E R Shelton and M Conti
Molecular Pharmacology October 1, 1995, 48 (4) 616-622;
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