METABOLISM AND FUNCTION OF CYCLIC NUCLEOTIDES

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Cyclic nucleotide phosphodiesterases (PDEs) serve the purpose of catalyzing and regulating the hydrolysis cAMP and cGMP and thereby the functions of these nucleotide second messengers. It is now known that several different gene families of PDEs exist in all species. In some cases the specific role(s) played by different PDE isozymes are known. However, in most tissues the role(s) for individual PDEs have not yet been determined. The recent realization that in many cells cyclic nucleotide levels oscillate rapidly has emphasized the importance of the PDEs for modulating not only the amplitude of a cyclic nucleotide signal but also its duration. A good example for a specific role played by a PDE in the modulation of rapid changes in cyclic nucleotides occurs in the photoreceptor outer segments. Here regulation of photoreceptor PDE activity controls the response of cGMP to changes in light intensity. These changes in cGMP in turn modulate the activity of a cGMP-gated cation channel in the photoreceptor outer segment membranes. We suggest in this application that other PDEs perform a similar function in the modulation of olfactory signal transduction and probably in other physiological processes that must rapidly respond to change. Three general types of experiments are described in this application. The first proposes to thoroughly characterize a new family of CaM-dependent PDEs that we have recently discovered to be highly expressed in olfactory neurons. The second proposes to determine if and how several different PDE families, including this new one, are involved in olfactory signal transduction. The third proposes to continue the search for new PDE isozyme variants both in olfactory neurons and other tissues. It is expected that the proposed studies will add to our knowledge about the mechanisms of regulation of olfactory sensory transduction. Since, some members of the PDE family are also expressed in other tissues, including specific regions of the brain, testis, and heart, it is expected that much of what we learn about the function of this family of isozymes in olfactory neurons will also be applicable to our understanding of the physiology of these other tissues. Finally, because different PDE isozymes are expressed in different cells, there is currently great interest in the pharmacological application of isozyme selective PDE inhibitors as therapeutic agents. It is expected that the development of the expression systems proposed in this application will also greatly aid in the development of these agents.