Historical Background
Cyclic 3′5′ adenosine monophosphate (cAMP) is a key second messenger that is responsible for regulating many pivotal signaling processes in all mammalian cell types (Tasken and Aandahl 2004). It influences cell growth, differentiation, shape, and movement as well as processes such a cardiac contraction, metabolism, water retention, learning, and memory. Most intriguingly, however, cAMP can selectively regulate a variety of very different processes in any one particular cell type. Indeed, uncovering the molecular mechanisms that allow cAMP to selectively regulate disparate processes within a single cell has provided a major challenge. Only very recently has the means whereby cAMP signaling is compartmentalized in cells begun to be understood (Tasken and Aandahl 2004; Baillie et al. 2005;Willoughby and Cooper 2007). One key requirement is for spatially discrete signaling complexes to be assembled in...
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Baillie GS, Scott JD, Houslay MD. Compartmentalisation of phosphodiesterases and protein kinase A: opposites attract. FEBS Lett. 2005;579:3264–70.
Bolger GB, Dunlop AJ, Meng D, Day JP, Klussmann E, Baillie GS, Adams DR, Houslay MD. Dimerization of cAMP phosphodiesterase-4 (PDE4) in living cells requires interfaces located in both the UCR1 and catalytic unit domains. Cell Signal. 2015;27:756–69.
Cedervall P, Aulabaugh A, Geoghegan KF, McLellan TJ, Pandit J. Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4. Proc Natl Acad Sci USA. 2015;112:E1414–22.
Cheung YF, Kan Z, Garrett-Engele P, Gall I, Murdoch H, Baillie GS, Camargo LM, Johnson JM, Houslay MD, Castle JC. PDE4B5, a novel, super-short, brain-specific cAMP phosphodiesterase-4 variant whose isoform-specifying N-terminal region is identical to that of cAMP phosphodiesterase-4D6 (PDE4D6). J Pharmacol Exp Ther. 2007;322:600–9.
Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007;76:481–511.
Havekes R, Park AJ, Tolentino RE, Bruinenberg VM, Tudor JC, Lee Y, Hansen RT, Guercio LA, Linton E, Neves-Zaph SR, Meerlo P, Baillie GS, Houslay MD, Abel T. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory. J Neurosci. 2016;36(34):8936–46. doi:10.1523/JNEUROSCI.0248-16.2016.
Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci. 2010;35:91–100.
Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 2003;370:1–18.
Houslay MD, Adams DR. Putting the lid on phosphodiesterase 4. Nat Biotechnol. 2010;28:38–40.
Houslay MD, Schafer P, Zhang KY. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005;10:1503–19.
Kaname T, Ki CS, Niikawa N, Baillie GS, Day JP, Yamamura K, Ohta T, Nishimura G, Mastuura N, Kim OH, Sohn YB, Kim HW, Cho SY, Ko AR, Lee JY, Kim HW, Ryu SH, Rhee H, Yang KS, Joo K, Lee J, Kim CH, Cho KH, Kim D, Yanagi K, Naritomi K, Yoshiura K, Kondoh T, Nii E, Tonoki H, Houslay MD, Jin DK. Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis. Cell Signal. 2014;26:2446–59.
Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs. Curr Pharm Des. 2010;16:1114–25.
Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol. 2012;165:1288–305.
Kim MJ, Park SK, Lee JH, Jung CY, Sung DJ, Park JH, Yoon YS, Park J, Park KG, Song DK, Cho H, Kim ST, Koo SH. Salt-inducible kinase 1 terminates cAMP signaling by an evolutionarily conserved negative-feedback loop in β-cells. Diabetes. 2015;64:3189–202.
Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther. 2006;109:366–98.
MacKenzie KF, Wallace DA, Hill EV, Anthony DF, Henderson DJ, Houslay DM, Arthur JS, Baillie GS, Houslay MD. Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. Biochem J. 2011;435(3):755–69. doi:10.1042/BJ20101184.
Mika D, Conti M. PDE4D phosphorylation: a coincidence detector integrating multiple signaling pathways. Cell Signal. 2016;28:719–24.
Murdoch H, Vadrevu S, Prinz A, Dunlop A, Klussmann E, Bolger GB, Norman JC, Houslay MD. LIS1/cAMP phosphodiesterase-4 (PDE4) interaction and their role in cytoplasmic dynein function. J Cell Sci. 2011;124:2253–66.
Plattner F, Hayashi K, Hernández A, Benavides DR, Tassin TC, Tan C, Day J, Fina MW, Yuen EY, Yan Z, Goldberg MS, Nairn AC, Greengard P, Nestler EJ, Taussig R, Nishi A, Houslay MD, Bibb JA. The role of ventral striatal cAMP signaling in stress-induced behaviors. Nat Neurosci. 2015;18:1094–100.
Serrels B, Sandilands E, Serrels A, Baillie G, Houslay MD, Brunton VG, Canel M, Machesky LM, Anderson KI, Frame MC. A complex between FAK, RACK1, and PDE4D5 controls spreading initiation and cancer cell polarity. Curr Biol. 2010;20(12):1086–92. doi:10.1016/j.cub.2010.04.042.
Sheppard CL, Lee LC, Hill EV, Henderson DJ, Anthony DF, Houslay DM, Yalla KC, Cairns LS, Dunlop AJ, Baillie GS, Huston E, Houslay MD. Mitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site phosphorylation, influences cell cycle progression. Cell Signal. 2014;26:1958–74.
Tasken K, Aandahl ME. Localized effects of cAMP mediated by distinct routes of protein kinase A. Physiol Rev. 2004;84:137–67.
Willoughby D, Cooper DM. Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev. 2007;87:965–1010.
Xie M, Blackman B, Scheitrum C, Mika D, Blanchard E, Lei T, Conti M, Richter W. The upstream conserved regions (UCRs) mediate homo- and hetero-oligomerization of type 4 cyclic nucleotide phosphodiesterases (PDE4s). Biochem J. 2014;459:539–50.
Zaccolo M. cAMP signal transduction in the heart: understanding spatial control for the development of novel therapeutic strategies. Br J Pharmacol. 2009;158:50–60.
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Houslay, M.D. (2018). PDE4. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_336
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DOI: https://doi.org/10.1007/978-3-319-67199-4_336
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