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Oral presentation

The amplitude and duration of cyclic nucleotide signals within the cell are modulated in large part by their rates of degradation by cyclic nucleotide phosphodiesterases (PDEs). Moreover, the PDEs must respond to both short-term acute signals and longer term adaptive needs. Importantly, it now appears that different cyclic nucleotide dependent processes are compartmentalized. Therefore, mechanisms have evolved to differentially control the degradation in these functional compartments over a wide range of time frames. This is accomplished in large part by the selective expression and localization of different isozymes of PDE. At present nearly 20 different PDE genes have been identified in mammalian species. Any particular cell type might express only 3 or 4 different PDEs, each of which has been chosen by the cell to display the most appropriate localization and regulatory properties necessary for the proper functioning of the cell type in which they are expressed.

In this talk I will discuss our current understanding of the number and regulatory properties of the various genes in the cyclic nucleotide PDE superfamily. As an example of rapid, short-term regulation of PDE activity I will present some of our recent progress on identification of the molecular determinants by which cGMP can allosterically regulate cyclic AMP hydrolysis. This will include details of the crystal structure of the cGMP binding sites in PDE2A. As an example of selective PDE expression I will also discuss current examples of changes in transcriptional expression of several cGMP PDE isozymes during the differential maturation of monocytes to various types of macrophages. Finally, I will discuss the question of why PDEs have developed very high affinity (nM) binding sites for cGMP on enzymes that are likely to exist in compartments that contain uM levels of cGMP.

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