Disruption of the cyclic AMP phosphodiesterase-4 (PDE4)–HSP20 complex attenuates the β-agonist induced hypertrophic response in cardiac myocytes

Sin, Yuan Yan; Edwards, Helen V.; Li, X.; Day, Jonathon P.; Frank, Christian; Dunlop, Allan J.; Adams, Dave; Zaccolo, Manuela; Houslay, Miles D.; Baillie, George S.

doi:10.1016/j.yjmcc.2011.02.006

Cited by 94 publications

(113 citation statements)

References 60 publications

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“…We show here that PDE inhibitors, which target specifically PDEs 4, 5 and 9, induce the phosphorylation of HSP20 in a dose‐ and time‐dependent manner. It is already known that HSP20 exists in a complex with AKAP‐Lbc 24 and PDE4D 11, and that dissociation of PDE4 from this signalosome results in the phosphorylation of HSP20, which acts to attenuate hypertrophic signalling in a heart failure model 25. In contrast, the direct association of PDE5 and PDE9 with HSP20 has not been investigated, yet our data suggest that the activities of these PDEs also influence the probability of HSP20 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1–42‐mediated cytotoxicity

et al. 2016

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Phosphodiesterase (PDE) inhibitors are currently under evaluation as agents that may facilitate the improvement of cognitive impairment associated with Alzheimer's disease. Our aim was to determine whether inhibitors of PDEs 4, 5 and 9 could alleviate the cytotoxic effects of amyloid beta 1–42 (Aβ1–42) via a mechanism involving the small heatshock protein HSP20. We show that inhibition of PDEs 4, 5 and 9 but not 3 induces the phosphorylation of HSP20 which, in turn, increases the colocalisation between the chaperone and Aβ1–42 to significantly decrease the toxic effect of the peptide. We conclude that inhibition of PDE9 is most effective to combat Aβ1–42 cytotoxicity in our cell model.

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Section: Discussionmentioning

confidence: 99%

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1–42‐mediated cytotoxicity

et al. 2016

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“…This peptide inhibited the interaction of HSP20 and PDE4D5 in HEK293 cells and increased the serine 16 phosphorylation. Moreover, in neonatal cardiac myocytes the peptide inhibited the isoproterenol-induced hypertrophy, it inhibited the isoproterenol-induced rise of the hypertrophy marker natriuretic peptide (ANP) by 50 % [56]. Moreover, in vivo in mice the peptides protected against cardiac remodelling after aortic banding, an animal model for heart failure [57,58].…”

Section: Pde4 Isozymes' Protein-protein Interactions As Drug Targets mentioning

confidence: 99%

“…Moreover, in neonatal cardiac myocytes the peptide inhibited the isoproterenol-induced hypertrophy, it inhibited the isoproterenol-induced rise of the hypertrophy marker natriuretic peptide (ANP) by 50 % [56]. Moreover, in vivo in mice the peptides protected against cardiac remodelling after aortic banding, an animal model for heart failure [57,58]. Thus the use of peptides suggests the interaction as a putative drug target for the treatment of heart failure, as cardiac hypertrophy represents an intermediate stage en route to heart failure.…”

Section: Pde4 Isozymes' Protein-protein Interactions As Drug Targets mentioning

confidence: 99%

“…Thus the use of peptides suggests the interaction as a putative drug target for the treatment of heart failure, as cardiac hypertrophy represents an intermediate stage en route to heart failure. Alanine scans of the PDE4D5 region interacting with HSP20 using peptide spots revealed critical amino acids whose substitution with alanine abolished the interaction (H470, H471 K477, E481, E482 and D485) [56]. These amino acids may be considered hot spots and thus could be the starting point for the development of small molecules blocking the interaction.…”

Section: Pde4 Isozymes' Protein-protein Interactions As Drug Targets mentioning

confidence: 99%

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Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

Klussmann

2016

Cellular Signalling

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The second messenger cyclic adenosine monophosphate (cAMP) is ubiquitous and directs a plethora of functions in all cells. Although theoretically freely diffusible through the cell from the site of its synthesis it is not evenly distributed. It rather is shaped into gradients and these gradients are established by phospodiesterases (PDEs), the only enzymes that hydrolyse cAMP and thereby terminate cAMP signalling upstream of cAMP's effector systems. Miles D.Houslay has devoted most of his scientific life highly successfully to a particular family of PDEs, the PDE4 family. The family is encoded by four genes and gives rise to around 20 enzymes, all with different functions. M. Houslay has discovered many of these functions and realised early on that PDE4 family enzymes are attractive drug targets in a variety of human diseases, but not their catalytic activity as that is encoded in conserved domains in all family members. He postulated that targeting the intracellular location would provide the specificity that modern innovative drugs require to improve disease conditions with fewer side effects than conventional drugs.Due to the wealth of M. Houslay's work, this article can only summarize some of his discoveries and, therefore, focuses on protein-protein interactions of PDE4. The aim is to discuss functions of selected protein-protein interactions and peptide spot technology, which M.Houslay introduced into the PDE4 field for identifying interacting domains. The therapeutic potential of PDE4 interactions will also be discussed.

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“…The protective phosphorylation is aided by HSP20's ability to complex with AKAP Lbc, bringing it within close proximity to PKA [42] . Conversely, the protective phosphorylation of HSP20 is attenuated by the chaperone's capacity to bind to members of the PDE4 family, including PDE4D5 [43]. Inhibitors of PDE4 activity promote the phosphorylation of HSP20 [44] and the localised nature of the PDE4-HSP20 complex has been demonstrated using cAMP reporters that are bound to the chaperone or are ubiquitously expressed in the cytoplasm of cells.…”

Section: Hsp20mentioning

confidence: 99%

Location, location, location: PDE4D5 function is directed by its unique N-terminal region

Wills

Ehsan

Whiteley

et al. 2016

Cellular Signalling

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Compartmentalised cAMP SignallingCharacterisation of the cyclic AMP signalling pathway in glycogenolysis as the first "second messenger" system opened the door for study of "cellular signalling" as a Depending on receptor type, cAMP produced at the cell membrane can reach far into the cell or stay localised to its site of production. The distance cAMP travels and its ability to form three-dimensional gradients, triggering activation of cAMP effectors, are determined by the phosphodiesterase (PDE) landscape [8]. Often, PDEs are expressed at low levels yet it is their localisation to demarcated positions within cells that underpins both their effectiveness and function. Indeed, reporter technology devised to visualise cAMP gradient formation following specific receptor activation [9] has confirmed that PDE positioning is crucial to the formation of multiple, simultaneous and spatially distinct cAMP gradients that drive defined physiological responses. PDE familiesPDEs are a vast super-family of distinct, highly regulated enzymes which can be classified based on primary structure into class I, II and III -the largest, class I,

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Disruption of the cyclic AMP phosphodiesterase-4 (PDE4)–HSP20 complex attenuates the β-agonist induced hypertrophic response in cardiac myocytes

Cited by 94 publications

References 60 publications

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1–42‐mediated cytotoxicity

Selective inhibition of phosphodiesterases 4, 5 and 9 induces HSP20 phosphorylation and attenuates amyloid beta 1–42‐mediated cytotoxicity

Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

Location, location, location: PDE4D5 function is directed by its unique N-terminal region

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