Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1)

Ca2+/calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1) is one of the key enzymes involved in the complex interactions between the cyclic nucleotide and Ca2+ second messenger systems. Currently, three genes encod e PDE1, and alternate splicing of these genes gives rise to functionally di fferent isozymes which exhibit distinct catalytic and regulatory properties . Some isozymes have similar kinetic and immunological properties but are d ifferentially regulated by Ca2+ and calmodulin. These isozymes also differ in their mechanism of regulation by phosphorylation. Analysis of various re gulatory reactions involving Ca2+ and cyclic adenosine monophosphate (cAMP) has revealed the importance of the time dependence of these reactions duri ng cell activation; however, no measurement is available for the time of oc currence of specific regulatory reactions, cAMP-signalling systems provide a pivotal centre for achieving crosstalk regulation by various signalling p athways. It has been proposed that polypeptide sequences enriched in prolin e (P), glutamate (E), serine (S) and threonine (T), known as PEST motifs, s erve as putative intramolecular signals for rapid proteolytic degradation b y calpains. Calpains are Ca2+-dependent cysteine proteases that regulate va rious enzymes, transcription factors and structural proteins through limite d proteolysis. Isozyme PDE1A2 has a PEST motif and acts as a substrate for m-calpain. In this paper, we have described PDE1A2 regulation by calpains a nd its physiological implications. cAMP is an important component of the si gnal transduction pathway and plays an integral role in various physiologic al processes such as gene transcription, various neuronal functions, cardia c muscle contraction, vascular relaxation, cell proliferation and a host of other functions. It is important to identify the cellular processes where PDE isoform(s) and cAMP response are altered. This will lead to better unde rstanding of the pathology of disease states and development of novel thera peutics. The different PDE1 isozymes, although similar in kinetic propertie s, can be distinguished by various pharmacological agents. Our recent under standing of the role of PDE1 inhibitors such as ginseng, dihydropyridine an tagonists and antiparkinsonian agents are described in this review. The exa ct function of PDE1 isozymes in various pathophysiological processes is not clear because most of the studies have been carried out in vitro; therefor e, it is essential that further research be directed to in vivo studies.