It is well recognized that cAMP has important and multiple regulatory roles in the development and function of many different cells. It is also known that cAMP, works largely through activation of cAMP-dependent protein kinases and/or the guanine nucleotide exchange protein, Epac. Moreover, in the last few years it has become clear that specific compartments are present in most cells that serve to organize and regulate specific cAMP-dependent processes in the cells. One of the most important mechanisms by which this regulation occurs is through selective activation or inhibition of distinct isozymes of cyclic nucleotide phosphodiesterases (PDEs) in the cell. Although over 100 different PDEs are known, any single cell type usually expresses less than half a dozen of them and any single compartment even fewer. Our current understanding is that a very small number of PDEs will serve to control a particular pool of cAMP or cGMP. Therefore, different PDEs can easily regulate different processes in the cell. It is the goal of the proposed studies to identify in several different cell types which processes and proteins in that cell are regulated by PDE8A and PDE8B. The PDE8 family is a relatively newly discovered PDE family that is specific for cAMP and has the unusual property of being completely insensitive to isobutylmethylxanthine (IBMX), a highly effective small molecule inhibitor of all other PDEs of this class. As a result PDE8s have until recently not been implicated as major regulators of cellular function. However, recent data from our group now show that they can be very important to regulation of cell function. Our new data shows that in addition to Leydig cells, PDE8s are highly expressed in liver hepatocytes, brown fat cells, and adrenal fasciculata cells. Since we now have available mice having the PDE8A and PDE8B genes disrupted, we are in position to determine the importance of these two PDEs to cellular function, despite the fact that selective small molecule inhibitors are not yet available. Therefore, we propose to determine which of the several functions known to be modulated by cAMP in each of these cell types are regulated by this PDE family and how they do so.
The proposed studies will explore the role of a newly discovered and previously unstudied family of cyclic nucleotide phosphodiesterases, the PDE8s on adrenal, liver, and brown fat function. Preliminary evidence suggests that these PDEs are major regulators of cAMP controlled functions in these cell types. It is expected that the proposed studies will tell us which processes are regulated and how the regulation occurs at the molecular level. Just as another specific form of PDE is the target of the drug Viagra, so also it is quite possible that PDE8s may become the targets of drugs useful for treating adrenal, liver and adipose tissue dysfunction once we understand how they function in each of these tissues.
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