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General Research Description:
Cyclic nucleotides are soluble second messengers found in all tissues
throughout the body. Many drugs, hormones, and other agents modify
physiological processes by causing changes in the steady state levels of
cAMP and cGMP in cells. Levels of these nucleotide second messengers
can be controlled by altering the activity of the cyclic nucleotide phosphodiesterases
(PDEs) that degrade them. These PDEs regulate many signaling pathways.
For instance, the transduction of photon capture in the outer segment of
a photoreceptor to changes in neurotransmitter release from the inner segment
of this neuron is known to require PDE6. Regulation of aldosterone
production by atrial natriuretic peptide and regulation of platelet aggregation
by endothelial relaxation factor also depend on different PDEs. Various
drugs that selectively inhibit individual PDE isozymes have different effects
on animals, suggesting specific physiological roles for each PDE.
Current evidence indicates that there are several related gene families that code for different phosphodiesterases. Each of these families contains more than one gene. Furthermore, each gene product is differentially spliced to yield different isozymes. This means that there are a large number of different PDEs, which can be expressed and regulated according to each tissueís function. A major focus of this laboratory has been to study the molecular mechanism for control of these isoenzymes, and to determine the physiological function of each. Many current projects relate to which cell types contain what isozyme, and how that particular isozyme contributes to the phenotype of the cell. In addition, the isolation of cDNAs for many of the isozymes has allowed a series of structure/function studies to be initiated. Finally, posttranslational modifications or protein/protein interactions regulate several of these isozymes. Studies are underway to determine how and to what extent these types of regulation are important to the physiological functions of the cells in which the phosphodiesterases are expressed.
A wide variety of experimental approaches are employed in this lab. Both in vivo and in vitro techniques are utilized. They vary from basic enzymology studies with tissue extracts to refined protein chemistry approaches using pure proteins obtained from overexpressing PDEs. Several students are using isolated cell culture models to test for roles of the PDEs in such diverse processes as synaptic plasticity and T cell function. In these studies, traditional approaches, such as use drugs which specifically inhibit individual PDEs, as well as more recent techniques of using antisense RNA, dominant negative mutants and gene disruption are being utilized.