Expression, intracellular distribution and basis for lack of catalytic activity of the PDE4A7 isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene

Johnston, Lee Ann; Erdoğan, Suat; Cheung, York Fong; Sullivan, Michael L.; Barber, Rachael; Lynch, Martin J.; Baillie, George S.; Heeke, Gino Van; Adams, David H.; Huston, Elaine; Houslay, Miles D.

doi:10.1042/bj20031662

Cited by 26 publications

(12 citation statements)

References 60 publications

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“…Nitraquazone was developed by Syntex as a PDE4 inhibitor for the treatment of inflammation in the mid 1980s [53], maintaining some structural similarities to the xanthine-derived PDE4 inhibitors. Nitraquazone represents a divergent class of PDE4 inhibitors, including nitraquazone (13), RS-17597 (14), CP-77059 (15), KF-17625 (16), and compound 17 developed by Almirall, many of which are more selective inhibitors for PDE4 than their xanthine cousins. Compound 17 belongs to a 2,5-dihydropyrazolo[4,3-c]quinolin-3-ones series and exhibited better selectivity versus PDE3 and low emetic potential [54].…”

Section: Chemical Classes Of Pde4 Inhibitorsmentioning

confidence: 99%

Phosphodiesterase-4 as a potential drug target

Zhang¹,

Ibrahim²,

Gillette³

et al. 2005

Expert Opinion on Therapeutic Targets

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Phosphodiesterase-4 (PDE4) is the predominant enzyme in some specific cell types that is responsible for the degradation of the second messenger, cAMP. Consequently, PDE4 plays a crucial role in cell signalling and, as such, it has been the target of clinical drug development of various indications, ranging from anti-inflammation to memory enhancement. In this review, the fundamental biological role of PDE4 in intracellular signalling, its tissue distribution and regulation are described. The historical development of various chemical classes of PDE4 inhibitors and the challenges that face these inhibitors as therapeutics are also discussed. Finally, recent advances in the structural biology of PDE4 and their complexes with various inhibitors, as well as its potential impact on the rational design of potent and selective PDE4 inhibitors, are presented.

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Section: Chemical Classes Of Pde4 Inhibitorsmentioning

confidence: 99%

Phosphodiesterase-4 as a potential drug target

Zhang¹,

Ibrahim²,

Gillette³

et al. 2005

Expert Opinion on Therapeutic Targets

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“…Thus "long" isoforms have UCR1 and UCR2, "short" isoforms lack UCR1, and "super-short" isoforms have just a truncated UCR2, whereas "dead-short" isoforms lack UCR1 and UCR2 and have an inactive catalytic unit that is both N-and C-terminally truncated ( Figure 2). 51,52 All PDE4 genes encode long isoforms, although only certain PDE4 genes encode types of short forms (Figure 2). …”

Section: "Pde4-ology"mentioning

confidence: 99%

cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System

Houslay

Baillie

Maurice

2007

Circulation Research

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Abstract-Cyclic AMP regulates a vast number of distinct events in all cells. Early studies established that its hydrolysisby cyclic nucleotide phosphodiesterases (PDEs) controlled both the magnitude and the duration of its influence. Recent evidence shows that PDEs also act as coincident detectors linking cyclic-nucleotide-and non-cyclic-nucleotide-based cellular signaling processes and are tethered with great selectively to defined intracellular structures, thereby integrating and spatially restricting their cellular effects in time and space. Although 11 distinct families of PDEs have been defined, and cells invariably express numerous individual PDE enzymes, a large measure of our increased appreciation of the roles of these enzymes in regulating cyclic nucleotide signaling has come from studies on the PDE4 family. Four PDE4 genes encode more than 20 isoforms. Alternative mRNA splicing and the use of different promoters allows cells the possibility of expressing numerous PDE4 enzymes, each with unique amino-terminal-targeting and/or regulatory sequences. Dominant negative and small interfering RNA-mediated knockdown strategies have proven that particular isoforms can uniquely control specific cellular functions. Thus the protein kinase A phosphorylation status of the ␤ 2 adrenoceptor and, thereby, its ability to switch its signaling to extracellular signal-regulated kinase activation, is uniquely regulated by PDE4D5 in cardiomyocytes. We describe how cardiomyocytes and vascular smooth muscle cells selectively vary both the expression and the catalytic activities of PDE4 isoforms to regulate their various functions and how altered regulation of these processes can influence the development, or resolution, of cardiovascular pathologies, such as heart failure, as well as various vasculopathies. (Circ Res. 2007;100:950-966.)

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“…Our study prompts us to propose that PDE4 has a signalling role other than solely its ability to degrade cAMP, namely in this instance to act as a signalling scaffold able to regulate dynamically LIS1 cellular regulation of dynein. This concept may also allow insight into why the widely expressed catalytically inactive PDE4A7 is generated, because it might perform a regulatory scaffolding role in another system (Horton et al, 1995;Johnston et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function

Murdoch

Vadrevu

Prinz

et al. 2011

Journal of Cell Science

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SummaryLIS1, a WD40 repeat scaffold protein, interacts with components of the cytoplasmic dynein motor complex to regulate dyneindependent cell motility. Here, we reveal that cAMP-specific phosphodiesterases (PDE4s) directly bind PAFAH1B1 (also known as LIS1). Dissociation of LIS1-dynein complexes is coupled with loss of dynein function, as determined in assays of both microtubule transport and directed cell migration in wounded monolayers. Such loss in dynein functioning can be achieved by upregulation of PDE4, which sequesters LIS1 away from dynein, thereby uncovering PDE4 as a regulator of dynein functioning. This process is facilitated by increased intracellular cAMP levels, which selectively augment the interaction of long PDE4 isoforms with LIS1 when they become phosphorylated within their regulatory UCR1 domain by protein kinase A (PKA). We propose that PDE4 and dynein have overlapping interaction sites for LIS1, which allows PDE4 to compete with dynein for LIS1 association in a process enhanced by the PKA phosphorylation of PDE4 long isoforms. This provides a further example to the growing notion that PDE4 itself may provide a signalling role independent of its catalytic activity, exemplified here by its modulation of dynein motor function. Journal of Cell Scienceanti-VSV agarose and immune complexes blotted for both the PDE4 proteins and LIS1-GFP. Specific co-capture of LIS1-GFP was observed in the immunoprecipitates (Fig. 1A).Where indicated, cells were treated with a combination of the adenylyl cyclase activator forskolin and the non-selective cyclic nucleotide phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine 2254 Journal of Cell Science 124 (13) Fig. 1. Interaction of LIS1 with PDE4 isoforms. (A)C-terminal GFP-tagged LIS1 (LIS1-GFP) was co-expressed in HEK293 cells with VSV-epitope-tagged long PDE4 isoforms, either PDE4B1 or PDE4D3. Single transfections of LIS1-GFP, PDE4B1-VSV or PDE4D3-VSV were also performed as controls. Cells were challenged with either vehicle or with 100mM forskolin and 100mM IBMX for 15 minutes prior to harvesting. Lysates were immunoprecipitated with anti-VSV agarose and immunoblotted with anti-LIS1 or anti-VSV antibodies. The relative expression levels of the indicated proteins in cell lysate are shown in the input lanes. (B)HEK293 cells were co-transfected with LIS1 and the GFP-tagged short PDE4B2 isoform. Cells were challenged as described for A and lysates treated with anti-LIS1 antibody. Immunoprecipitates and input lysates were probed with GFP or LIS1 antisera. (C)Non-transfected HEK293 cells were treated as for A and cell lysates treated with PDE4B2-specific or PDE4D5-specific antibodies. Co-precipitated LIS1 was visualised using anti-LIS1 antibody (upper panels). The relative expression levels of LIS1, PDE4D5 and PDE4B2 in cell lysates were determined by specific immunoblotting. (D)HEK293 cells were transfected to coexpress LIS1-GFP with wild-type PDE4D3-VSV (i,ii) or the PDE4D3-VSV mutants, PDE4D3-S54A (i), PDE4D3-S13A (i) and PDE4D3-R51A,R52A (ii). Cell...

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Expression, intracellular distribution and basis for lack of catalytic activity of the PDE4A7 isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene

Cited by 26 publications

References 60 publications

Phosphodiesterase-4 as a potential drug target

Phosphodiesterase-4 as a potential drug target

cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System

Interaction between LIS1 and PDE4, and its role in cytoplasmic dynein function

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