In this report we have reviewed the progress made in the last 4 years toward understanding the structure and function of cyclic nucleotide PDEs. Major strides have been made in identifying the different forms present in human and other mammalian species, and tools to study the details of the expression in different cells and tissues have become available. The structure of the genes encoding PDEs is under investigation, and it is probable that the mechanism regulating PDE gene expression in different cells will be soon identified. The progress made in elucidating the short-term regulation of PDEs via phosphorylation will help understand the hormone action and is providing important clues about the structure of the different PDE domains. The possible role of PDEs in the control of hormonal responses and in the hormonal regulation of the cell cycle has been discussed and several questions are still unanswered. It is certain that, in the coming years, the question of whether the disruption of PDE function is the cause of inherited disorders will be addressed since most of the molecular tools are now available to explore this possibility. Although not discussed here, major strides have been made in synthesizing and testing PDE inhibitors. The progress in the pharmacology of the PDE may have a major impact in fields outside the ones where PDE inhibitors traditionally have been used. Until now, PDE inhibitors have found application in the treatment of cardiovascular disorders, in the control of airway contractility, and in the stimulation of the central nervous system (17). The possibility of using PDE inhibitors to manipulate the secretion or function of the endocrine organs has been precluded by the side effects of nonselective inhibitors. The discovery of a large number of isoforms and the generation of form-specific inhibitors will increase the selectivity of the pharmacological manipulation of PDE to the point that new areas of use of these compounds are becoming feasible. With the synthesis of more selective inhibitors it may soon become possible to stimulate the function of an endocrine organ or to manipulate the sensitivity to circulating hormones without affecting other functions. Endocrine cell secretion may also be manipulated using PDE inhibitors, as it has been shown that glucose-dependent insulin secretion can be manipulated with PDE inhibitors. Thus, the use of these form-selective inhibitors to manipulate endocrine organ function might open a new, exciting field of investigation.
|Number of pages||20|
|Publication status||Published - 1995|
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism