Calmodulin-dependent cyclic nucleotide phosphodiesterase (PDE1)

Abstract

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 encode PDE1, and alternate splicing of these genes gives rise to functionally different isozymes which exhibit distinct catalytic and regulatory properties. Some isozymes have similar kinetic and immunological properties but are differentially regulated by Ca2+ and calmodulin. These isozymes also differ in their mechanism of regulation by phosphorylation. Analysis of various regulatory reactions involving Ca2+ and cyclic adenosine monophosphate (cAMP) has revealed the importance of the time dependence of these reactions during cell activation; however, no measurement is available for the time of occurrence of specific regulatory reactions. cAMP-signalling systems provide a pivotal centre for achieving crosstalk regulation by various signalling pathways. It has been proposed that polypeptide sequences enriched in proline (P), glutamate (E), serine (S) and threonine (T), known as PEST motifs, serve as putative intramolecular signals for rapid proteolytic degradation by calpains. Calpains are Ca(2+)-dependent cysteine proteases that regulate various enzymes, transcription factors and structural proteins through limited 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 and its physiological implications. cAMP is an important component of the signal transduction pathway and plays an integral role in various physiological processes such as gene transcription, various neuronal functions, cardiac 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 understanding of the pathology of disease states and development of novel therapeutics. The different PDE1 isozymes, although similar in kinetic properties, can be distinguished by various pharmacological agents. Our recent understanding of the role of PDE1 inhibitors such as ginseng, dihydropy-ridine antagonists and antiparkinsonian agents are described in this review. The exact function of PDE1 isozymes in various pathophysiological processes is not clear because most of the studies have been carried out in vitro; therefore, it is essential that further research be directed to in vivo studies.

Restoration of Neuronal Plasticity by a Phosphodiesterase Type 1 Inhibitor in a Model of Fetal Alcohol Exposure

“…A possible explanation for an alteration of cAMP levels after early alcohol exposure is related to the upregulation of calmodulin (CaM) that has been demonstrated to occur after chronic alcohol exposure (Pant et al, 1985;Hamoudi et al, 1995). Increase in CaM can result in an enhancement of PDE1 activity and a consequent decrease on cAMP (Kakkar et al, 1999). In fact, it has been shown recently that an increase in calcineurin levels, which can enhance PDE1 activity as well, impairs ocular dominance plasticity (Yang et al, 2005).…”

The opposite correlation between calcium ion and cyclic-AMP regarding the activation of microsomal triglyceride transfer protein in rat liver

“…Thirdly, as cAMP and Ca 2+ have opposite effects on MTP activity, it can be inferred that Ca 2+ /calmodulin-activated phosphodiesterase (PDE)-1A2 (21), an isozyme of PDE, is involved in MTP activation by stimulating the degradation of cAMP. This could be due to the inhibition of Ca 2+ -or Ca 2+ /calmodulin-elevated MTP activity by the intracellular Ca 2+ chelator BAPTA-AM, the extracellular Ca 2+ chelator EDTA, or the calmodulin antagonist W-7 (7,8).…”

cAMP-Dependent Protein Kinase Mediates Activity-Regulated Synaptic Targeting of NMDA Receptors

“…6) suggests that PKA functions downstream of activity blockade. Decreased calcium entry through NMDA receptors could potentially activate PKA through decreased activity of a calcium/calmodulin-activated phosphodiesterase of the PDE1 family (Zhao et al, 1997;Kakkar et al, 1999). These enzymes are highly expressed in neurons, including hippocampal pyramidal neurons, are present in the postsynaptic density (Grab et al, 1981), and are targets of the inhibitor IBMX used in this study (Fig.…”