Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene

Bolger, B. Graeme; Erdoğan, Suat; Jones, Eldon M.; Loughney, Kate; Scotland, Grant; Hoffmann, Ralf; Wilkinson, Ian; Farrell, Cathy A.; Houslay, Daniel M.

doi:10.1042/bj3280539

Cited by 174 publications

(244 citation statements)

References 47 publications

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“…Sheep polyclonal antisera were used to detect individual PDE4 subfamilies (24 -28). PDE4D also was stained with monoclonal mouse antibodies (gift from Dr. Sharron Wolda, ICOS, Bothell, WA) (24,27,28). The PKA-phosphorylated serine within upstream conserved region 1 (UCR1) of PDE4 was detected with rabbit antiserum PS54-UCR1-A1 (29).…”

Section: Immunofluorescence and Immunogold Electron Microscopymentioning

confidence: 99%

Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D Is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells

Stefan

Wiesner

Baillie

et al. 2007

Journal of the American Society of Nephrology

134

127

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A ntidiuretic hormone (arginine vasopressin [AVP]) induces fusion of vesicles that contain the water channel aquaporin-2 (AQP2) with the plasma membrane of renal collecting duct principal cells. This "AQP2 shuttle" increases the osmotic water permeability (Pf) of the cells, facilitating water reabsorption from the collecting duct (1). The AQP2 shuttle is initiated upon binding of AVP to vasopressin-2 receptors (V2R) and triggered by the consequent cAMP elevation and protein kinase A (PKA) activation. It is the PKA phosphorylation of AQP2 that elicits redistribution of AQP2-bearing vesicles. Pivotal to this redistribution is the compartmentalization of PKA by A kinase anchoring proteins (AKAP) (2). Phosphodiesterases (PDE), which are the sole means of degrading cAMP, are poised to regulate PKA signaling (3-6). The PDE4 family has attracted great interest because of its link to stroke (7), schizophrenia (8), and the therapeutic potential of selective inhibitors for treating inflammatory diseases (9-12). The four subfamilies (PDE4A through D) are encoded by separate genes, generating approximately 20 isoforms (9,11) that can interact with scaffolding proteins, including AKAP and ␤-arrestin (12-16), positioning them for a role in compartmentalized cAMP/PKA signaling.Here we show that compartmentalization of cAMP/PKA signaling by PDE4 is involved in the regulation of the AQP2 shuttle and the Pf. This is of particular pertinence because PDE4 hyperactivity causes nephrogenic diabetes insipidus in a mouse model (17).

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Section: Immunofluorescence and Immunogold Electron Microscopymentioning

confidence: 99%

Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D Is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells

Stefan

Wiesner

Baillie

et al. 2007

Journal of the American Society of Nephrology

134

127

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“…Bradford reagent was from Bio-Rad. Monoclonal antibodies specific to each of the four PDE4 subfamilies were a kind gift from Dr. Sharon Wolda (ICOS Corp.), as described previously (27)(28)(29)(30). Hek-B2 cells were a kind gift from Prof. Graeme Milligan (University of Glasgow) (31).…”

Section: Methodsmentioning

confidence: 99%

“…Mammalian Cell Expression Constructs-The full-length cDNAs encoding human PDE4D3 (GenBank TM L20970) and PDE4D5 (GenBank TM AF012073) as well as various truncated constructs of PDE4D5, all with a carboxyl-terminal VSV epitope tag, were cloned into pcDNA3 (Invitrogen) for expression in mammalian cells under the control of the cytomegalovirus intermediate early gene promoter, as we have reported previously (27,32). pcDNA3NARB2FLAG, encoding human wild type, carboxyl-terminal FLAG epitope-tagged ␤-arrestin 2 in pcDNA3, was used as described previously (25).…”

Section: Methodsmentioning

confidence: 99%

The Unique Amino-terminal Region of the PDE4D5 cAMP Phosphodiesterase Isoform Confers Preferential Interaction with β-Arrestins

Bolger

McCahill

Huston

et al. 2003

Journal of Biological Chemistry

101

139

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Isoproterenol challenge of Hek-B2 cells causes a transient recruitment of the endogenous PDE4D isoforms found in these cells, namely PDE4D3 and PDE4D5, to the membrane fraction. PDE4D5 provides around 80% of the total PDE4D protein so recruited, although it only comprises about 40% of the total PDE4D protein in Hek-B2 cells. PDE4D5 provides about 80% of the total PDE4D protein found associated with ␤-arrestins immunopurified from Hek-B2, COS1, and A549 cells as well as cardiac myocytes, whereas its overall level in these cells is between 15 and 50% of the total PDE4D protein. Truncation analyses indicate that two sites in PDE4D5 are involved in mediating its interaction with ␤-arrestins, one associated with the common PDE4 catalytic region and the other located within its unique amino-terminal region. Truncation analyses indicate that two sites in ␤-arrestin 2 are involved in mediating its interaction with PDE4D5, one associated with its extreme amino-terminal region and the other located within the carboxylterminal domain of the protein. We suggest that the unique amino-terminal region of PDE4D5 allows it to preferentially interact with ␤-arrestins. This specificity appears likely to account for the preferential recruitment of PDE4D5, compared with PDE4D3, to membranes of Hek-B2 cells and cardiac myocytes upon challenge with isoproterenol.The heptahelical ␤-adrenergic receptors (␤ 2 ARs) 1 act by coupling through the G-protein G s to stimulate adenylyl cyclase and thereby increase intracellular cAMP concentrations (1-4). It is now well established that the rapid uncoupling of this response is achieved by the action of the G-protein receptorcoupled kinase 2 (2). This phosphorylates the carboxyl-terminal tail of the plasma membrane-associated ␤ 2 AR, allowing the recruitment of ␤-arrestins from the cytosol (5-7). It is this recruitment of ␤-arrestin, rather than phosphorylation per se, that elicits uncoupling, presumably by sterically blocking coupling of the ␤ 2 AR to G s . The importance of ␤-arrestin interaction to G-protein-coupled receptors (GPCRs) in vivo has been clearly established in knockout mouse models (8 -10).The attenuation of cAMP signaling is also achieved through the action of phosphodiesterases (PDEs) that are able to hydrolyze cAMP to 5Ј-AMP (11-17). Since they provide the sole route for degradation of cAMP in cells, they are poised to play a key role in controlling cAMP signaling. Multiple genes encode a large superfamily of PDEs, which differ in their regulatory and kinetic properties. Of these, the PDE4 cAMP-specific phosphodiesterase family (13-16) has recently attracted much interest, since PDE4-selective inhibitors are currently being developed as potential therapeutic agents for various inflammatory diseases of the respiratory system, such as asthma and chronic obstructive pulmonary disease (18 -21). The PDE4 enzyme family is encoded by four genes (PDE4A, -B, -C, and -D), which generate over 16 different isoforms through the use of distinct promoters and alternative mRNA splicing (12,13,...

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“…Two different structures of these variants can be distinguished, short forms (65-75 kDa) and long forms . The difference between short and long forms lies in the N-terminal region, at the level of UCR1 and UCR2 (upstream conserved regions): short forms are truncated at UCR2 and long forms have both UCR1 and UCR2 (Bolger et al 1997). The different PDE4 subtypes are differently expressed depending on the tissue.…”

Section: Strategies To Avoid Side-effects Induced By Oral Pde4 Inhibimentioning

confidence: 99%

Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

Lagente

Martin-Chouly

Boichot

et al. 2005

Mem. Inst. Oswaldo Cruz

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Phosphodiesterases (PDEs) The selective targeting of phosphodiesterases type 4 (PDE4) has been actively pursued as a novel therapeutic approach in the treatment of respiratory diseases associated with inflammatory processes such as asthma and chronic obstructive pulmonary disease (COPD). The rationale for their use in respiratory disease is based on the clinical efficacy of non-selective PDE inhibitors such as theophylline, the detection of PDE4 in many of the cells involved in these diseases and the emergence of positive results from a number of pharmacological studies and clinical trials currently evaluating the efficacy of selective PDE4 inhibitors in respiratory diseases (Barnette 1999, Spina 2000. PDE4 represent the major class of PDE expressed in human inflammatory cells (Wang et al. 1999) and in particular in macrophages, eosinophils and neutrophils, the main cell types present in the lungs of asthmatic and COPD patients.PDE4 are members of the phosphodiesterase (PDE) superfamily of enzymes, which comprises at least 11 members hydrolyzing cyclic AMP (adenosine 3',5'-cyclic monophosphate) and/or cyclic GMP (guanosine 3',5'-cyclic monophosphate) (Houslay et al. 1998, Conti & Jin 1999, Giembycz 2000. In the case of PDE4, there are four gene products and multiple splice variants resulting in a variety of PDE4 isoforms. PDE4 selectively catalyse the hydrolysis of cAMP and the anti-inflammatory effects of selective PDE4 inhibitors were supposed to result of the reduction of cAMP hydrolysis. However, some recent studies have demonstrated that PDE4 could also act through cAMP-independent mechanisms. Indeed, we have observed that PDE4 inhibitors triggered a cAMP-independent inhibition of fMLP-induced O 2. -release from bronchoalveolar lavage cells of rats exposed to lipopolysaccharide . We also showed that the inhibitory effect of PDE4 inhibitors on O 2. -production is mediated by the activation of p44/42 MAPK and that PDE4 inhibit p44/42 MAPK by a direct interaction ). This study allowed us to identify a novel mechanism involving MAPK in the pathway connecting PDE4 to fMLP-induced O 2. -generation in neutrophils.

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Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene

Cited by 174 publications

References 47 publications

Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D Is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells

Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D Is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells

The Unique Amino-terminal Region of the PDE4D5 cAMP Phosphodiesterase Isoform Confers Preferential Interaction with β-Arrestins

Selective PDE4 inhibitors as potent anti-inflammatory drugs for the treatment of airway diseases

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