Regulation of calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1): Review

Abstract

The response of living cells to change in cell environment depends on the action of second messenger molecules. The two second messenger molecules cAMP and Ca 2+ regulate a large number of eukaryotic cellular events. Calmodulin-stimulated cyclic nucleotide phosphodiesterase (PDE1) is one of the key enzymes involved in the complex interaction between cAMP and Ca 2+ second messenger systems. Some PDE1 isozymes have similar kinetic and immunological properties but are differentially regulated by Ca 2+ and calmodulin. Accumulating evidence suggests that the activity of PDE1 is selectively regulated by cross-talk between Ca 2+ and cAMP signalling pathways. These isozymes are also further distinguished by various pharmacological agents. We have demonstrated a potentially novel regulation of PDE1 by calpain. This study suggests that limited proteolysis by calpain could be an alternative mechanism for the activation of PDE1. We have also shown PDE1 activity, expression and effect of calpain in the rat model in vitro of cardiac ischemiareperfusion. Contents 1. Introducton 2. Kinetic properties of various PDE1 isozymes 3. Differential regulation of PDE1 by CaM and Ca 2+ 4. Coupling between Ca 2+ and cAMP second messengers in the regulation of PDE1 5. Role of autophosphorylation of PDE1B1 by CaMdependent protein kinase II 6. Differential inhibition of PDE1 isozymes and its therapeutic applications 7. Role of proteolysis in regulating PDE1A2 8. Role of PDE1A1 in ischemic-reperfused heart 9. Conclusion

Cytokine-Induced S-Nitrosylation of Soluble Guanylyl Cyclase and Expression of Phosphodiesterase 1A Contribute to Dysfunction of Longitudinal Smooth Muscle Relaxation

“…PDE1A hydrolyzes cGMP with much higher affinity than cAMP, and the activity of PDE1 family members, including PDE1A, is stimulated by Ca 21 /calmodulin, albeit with different affinities. PDE1A has higher affinity for calmodulin and is stimulated at much lower concentrations of Ca 21 than the other isozymes (Sharma et al, 2006). Induction of PDE1A activity leading to a decrease in cGMP levels in response to cytokines could also contribute to the hypercontractile response of longitudinal muscle during inflammation.…”

“…PDE5 expression is abundant in smooth muscle and plays an important role in the regulation of cGMP levels and smooth muscle relaxation (Murthy, 2001;Mahavadi et al, 2013). PDE1 (PDE1A and PDE1B) hydrolyzes cGMP with higher affinity and is regulated by Ca 21 /calmodulin (Sharma et al, 2006). Both PDE2 and PDE3 (PDE3A and PDE3B) hydrolyze cAMP and cGMP with similar affinity, but due to a higher catalytic rate of PDE3 for cAMP than cGMP, cGMP acts as a competitive inhibitor, and PDE3 is known as cGMP-inhibited cAMP phosphodiesterase (Ahmad et al, 2012).…”

“…PDE5, -6, and -9 are specific for cGMP, whereas PDE1, -2, and -3 hydrolyze both cAMP and cGMP, albeit with different affinity (Sharma et al, 2006;Ahmad et al, 2012). PDE5 is a dimer with cGMP-binding sites in its regulatory N-terminal and catalytic C-terminal domains (Soderling and Beavo, 2000;Francis et al, 2001;Rybalkin et al, 2003;Corbin et al, 2009).…”

Cross-regulation of Phosphodiesterase 1 and Phosphodiesterase 2 Activities Controls Dopamine-mediated Striatal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Trafficking

“…This is an important question, as enhancing the basal cellular levels of cGMP may not be sufficient to support PDE2 activation. A possible candidate is PDE1, an MSN-enriched PDE with a preference for cGMP (24,45). We explored the role of PDE1 in AMPAR trafficking by varying the concentrations of PDE1 and PDE2 and plotting the AUC of the resulting time courses of GluA1 surface insertion as a function of PDE2 and PDE1 concentration (Fig.…”

BK channel regulation by phosphodiesterase type 1: a novel signaling pathway controlling human detrusor smooth muscle function

“…In addition, the mAChR signaling pathways are subjected to positive feedback regulation by PDEs, particularly the Ca 2ϩ -activated PDE type 1 isoform (PDE1) (5,6,20). PDE1, the only PDE isoform that is activated by Ca 2ϩ (5,6), is considered to be an important mediator of the cross talk between intracellular cAMP and Ca 2ϩ signaling pathways in the regulation of DSM excitability (23). An increase in intracellular Ca 2ϩ is often accompanied by a reduction of intracellular cAMP levels due to the Ca 2ϩ -dependent PDE1 activation (5,7).…”