PDE4A

What is PDE4A protein?

PDE4A (phosphodiesterase 4A) gene is a protein coding gene which situated on the short arm of chromosome 19 at locus 19p13. The PDE4 enzyme belongs to a family of cAMPdependent PDEs that provide the major means of inactivating the key intracellular second messenger, cAMP. Four genes (4A, 4B, 4C, and 4D) encode around 20 distinct isoform members of the PDE4 family. The gene encodes one member of PDE4 family. The PDE4A protein is consisted of 886 amino acids and its molecular mass is approximately 98.1 kDa.

What is the function of PDE4A protein?

The PDE4A protein belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This PDE hydrolyzes the second messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes.

Fig1. Proposed model for the role of p75NTR in the cAMP-mediated plasminogen activation. (Benjamin D Sachs, 2007)

PDE4A Related Signaling Pathway

PDE4A is mainly involved in the regulation of cAMP (cyclic adenosine phosphate) signaling pathway. By specifically degrading cAMP, PDE4A regulates the concentration and duration of cAMP, and affects the downstream signal transduction of cAMP. In addition, PDE4A also interacts with other signaling pathways, such as MAPK/ERK, PI3K/AKT, and Wnt/β-catenin, which play important roles in cell growth, survival, and stress response.

PDE4A Related Diseases

PDE4A plays a key role in cardiovascular disease, including heart failure, myocardial infarction and hypertension. In addition, PDE4A has also been linked to neurological disorders such as Alzheimer's disease and Parkinson's disease. In these diseases, overactivation of PDE4A may lead to neuronal damage and death. Finally, PDE4A is also implicated in certain cancers because it can regulate the proliferation and survival of cancer cells.

Bioapplications of PDE4A

The most significant application of PDE4A is as a drug target. It is also used in clinical diagnosis, such as as a biomarker for certain inflammatory diseases to help doctors diagnose and monitor the disease.

Case study 1: Wito Richter, 2011

PDE4 isoenzymes are critical in the control of cAMP signaling in rodent cardiac myocytes. Ablation of PDE4 affects multiple key players in excitation-contraction coupling and predisposes mice to the development of heart failure. As little is known about PDE4 in human heart, the researchers explored to what extent cardiac expression and functions of PDE4 are conserved between rodents and humans. They find considerable similarities including comparable amounts of PDE4 activity expressed, expression of the same PDE4 subtypes and splicing variants, anchoring of PDE4 to the same subcellular compartments and macromolecular signaling complexes, and downregulation of PDE4 activity and protein in heart failure. As a consequence, the effect of PDE4 inactivation is different in rodents and humans. PDE4 inhibition leads to increased phosphorylation of virtually all PKA substrates in mouse cardiomyocytes, but increased phosphorylation of only a restricted number of proteins in human cardiomyocytes. These findings suggest that PDE4s have a similar role in the local regulation of cAMP signaling in rodent and human heart. However, inhibition of PDE4 has 'global' effects on cAMP signaling only in rodent hearts, as PDE4 comprises a large fraction of the total cardiac PDE activity in rodents but not in humans.

Fig1. Expression of PDE4 subtypes in rodent and human heart.

Fig2. Detection of macromolecular signaling complexes involving PDE4 in the human heart.

Case study 2: Ewa Kolosionek, 2009

Epithelial-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-beta1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-beta1-induced EMT in the human alveolar epithelial type II cell line A549. Interestingly, TGF-beta1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-beta1-stimulated cells. And the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. Collectively, the findings presented herein suggest that TGF-beta1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells.

Fig3. siRNA-mediated knockdown of PDE4A and PDE4D.

Fig4. Effects of PDE4 overexpression in inducing epithelial mesenchymal transition.

PDE4A has several biochemical functions, for example, 3,5-cyclic-AMP phosphodiesterase activity,cAMP binding,metal ion binding. Some of the functions are cooperated with other proteins, some of the functions could acted by PDE4A itself. We selected most functions PDE4A had, and list some proteins which have the same functions with PDE4A. You can find most of the proteins on our site.

PDE4A has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PDE4A here. Most of them are supplied by our site. Hope this information will be useful for your research of PDE4A.

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