In vitro PKA phosphorylation‐mediated human PDE4A4 activation

Liu, Susana; Gorseth, Elise; Bobechko, Brian P.; Bartlett, Adrienne J.; Lario, Paula I.; Gresser, Michael J.; Huang, Zheng

doi:10.1016/s0014-5793(02)02259-7

Cited by 24 publications

(25 citation statements)

References 38 publications

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“…Stimulation of the ␤ 2 -adrenoceptor also rapidly recruits ␤-arrestins with bound PDE4s to the plasma membrane within minutes as part of the desensitization machinery to limit the spread of the cAMP pool (Baillie et al, 2003). Some PDE4s are associated with PKA via protein kinase A anchoring proteins and/or activated by PKA-mediated phosphorylations, which provide additional controls to ensure a localized cAMP signaling through PDE4 regulation (Laliberte et al, 2002;Conti et al, 2003). Despite its lower abundance in T84 cells, PDE3 inhibition by trequinsin seems to be a more effective activator of iodide efflux with a quicker response, compared with that from PDE4 inhibition by Cpd-A under an identical AC state.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Activation of Cystic Fibrosis Transmembrane Conductance Regulator by Type 3 and Type 4D Phosphodiesterase Inhibitors

Liu¹,

Veilleux²,

Zhang³

et al. 2005

J Pharmacol Exp Ther

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The diseases of cystic fibrosis, chronic obstructive pulmonary disease (COPD), and chronic bronchitis are characterized by mucus-congested and inflamed airways. Anti-inflammatory agents that can simultaneously restore or enhance mucociliary clearance through cystic fibrosis transmembrane conductance regulator (CFTR) activation may represent new therapeutics in their treatment. Herein, we report the activation of CFTR-mediated chloride secretion by phosphodiesterase (PDE) 4 inhibitors in T84 monolayer using (125)I anion as tracer. In the absence of forskolin, the iodide secretion was insensitive to PDE4 inhibitor L-826,141 [4-[2-(3,4-bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-ethyl]-3-methylpyridine-1-oxide], roflumilast, or to PDE3 inhibitor trequinsin. However, these inhibitors potently augmented iodide secretion after forskolin stimulation, with efficacy coupled to the activation states of adenylyl cyclase. The iodide secretion from PDE3 or PDE4 inhibition was characterized at first by a prolonged efflux duration, followed by progressively elevated peak efflux rates at higher inhibitor concentrations. Paralleled with an increased phosphor-cAMP response element-binding protein formation, the CFTR activation dissociated from a global cAMP elevation and was blocked by H89 [N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide]. 2-(4-Fluorophenoxy)-N-[(1S)-1-(4-methoxyphenyl)ethyl]nicotinamide, a stereoselective PDE4D inhibitor, augmented iodide efflux more efficiently than its less potent (R)-isomer. The peak efflux from maximal PDE4 and PDE3 inhibition matched that from full adenylyl cyclase activation. These data suggest that PDE3 and PDE4 (mainly PDE4D) form the major cAMP diffusion barrier in T84 cells to ensure a compartmentalized CFTR signaling. Together with their potent anti-inflammatory properties, the potentially enhanced airway mucociliary clearance from CFTR activation may have contributed to the efficacy of PDE4 inhibitors in COPD and asthmatic patients. PDE4 inhibitors may represent new opportunities to combat cystic fibrosis and other respiratory diseases in future.

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Section: Discussionmentioning

confidence: 99%

Dynamic Activation of Cystic Fibrosis Transmembrane Conductance Regulator by Type 3 and Type 4D Phosphodiesterase Inhibitors

Liu¹,

Veilleux²,

Zhang³

et al. 2005

J Pharmacol Exp Ther

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“…It is worth noting that the Ser and surrounding residues found in PDE4D3 are not only present in all mammalian PDE4 long splicing variants but are also conserved through evolution from C. elegans to human, thus implying a critical function for this domain. Phosphorylation of this site also causes a variable increase in activity in other long PDE4 variants in overexpression systems (26,27). Activation of native PDE4D3 and PDE4D5 by phosphorylation has been demonstrated in vascular smooth muscle and lymphocytic cell lines (18,28,29).…”

Section: Pde4 Regulation By Pka-mediated Phosphorylationmentioning

confidence: 99%

Cyclic AMP-specific PDE4 Phosphodiesterases as Critical Components of Cyclic AMP Signaling

Conti

Richter

Méhats

et al. 2003

Journal of Biological Chemistry

452

411

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“…3,15,16 PKA phosphorylation of the long forms PDE4A4 and PDE4D3 causes their activation probably through disruption of UCR1-UCR2 interaction and UCR2 association with the catalytic region. 18,19,128,129 ERK phosphorylates a consensus motif, RXSP, in cooperation with a kinase interaction motif (KIM) situated within the catalytic domains of PDE4B, PDE4C, and PDE4D. 16 ERK phosphorylation of the long form PDE4D3 reduces cAMP-hydrolytic activity (ca.…”

Section: Enzymatic Regulation Of Pdes By Phosphorylation and Associatmentioning

confidence: 99%

Overview of PDEs and Their Regulation

Omori

Kotera

2007

Circulation Research

669

561

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Abstract-Contraction and relaxation of vascular smooth muscle and cardiac myocytes are key physiological events in the cardiovascular system. These events are regulated by second messengers, cAMP and cGMP, in response to extracellular stimulants. The strength of signal transduction is controlled by intracellular cyclic nucleotide concentrations, which are determined by a balance in production and degradation of cAMP and cGMP. Degradation of cyclic nucleotides is catalyzed by 3Ј,5Ј-cyclic nucleotide phosphodiesterases (PDEs), and therefore regulation of PDEs hydrolytic activity is important for modulation of cellular functions. Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties, and sensitivity to inhibitors. PDE families contain many splice variants that mostly are unique in tissue-expression patterns, gene regulation, enzymatic regulation by phosphorylation and regulatory proteins, subcellular localization, and interaction with association proteins. Each unique variant is closely related to the regulation of a specific cellular signaling. Thus, multiple PDEs function as a particular modulator of each cardiovascular function and regulate physiological homeostasis. (Circ Res. 2007;100:309-327.)

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In vitro PKA phosphorylation‐mediated human PDE4A4 activation

Cited by 24 publications

References 38 publications

Dynamic Activation of Cystic Fibrosis Transmembrane Conductance Regulator by Type 3 and Type 4D Phosphodiesterase Inhibitors

Dynamic Activation of Cystic Fibrosis Transmembrane Conductance Regulator by Type 3 and Type 4D Phosphodiesterase Inhibitors

Cyclic AMP-specific PDE4 Phosphodiesterases as Critical Components of Cyclic AMP Signaling

Overview of PDEs and Their Regulation

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