Compartmentalized Cyclic Adenosine 3′,5′-Monophosphate at the Plasma Membrane Clusters PDE3A and Cystic Fibrosis Transmembrane Conductance Regulator into Microdomains

Penmatsa, Himabindu; Zhang, Weiqiang; Yarlagadda, Sunitha; Li, Chunying; Conoley, Veronica G.; Yue, Junming; Bahouth, Suleiman W.; Buddington, Randal K.; Zhang, Guangping; Nelson, Deborah J.; Sonecha, Monal D.; Manganiello, Vincent; Wine, Jeffrey J.; Naren, Anjaparavanda P.

doi:10.1091/mbc.e09-08-0655

Cited by 63 publications

(106 citation statements)

References 67 publications

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“…Inhibition of PDE4, but not PDE1, stimulated Cl -secretion by ADPKD cells (Figure 3) and promoted cyst-like dilations in Pkd1 2 /2 mouse embryonic kidneys ( Figure 4). Although PDE3 has been shown to be functionally coupled to Cl -secretion by shark rectal glands 41 and pig trachea submucosal glands, 42 we found that PDE3 inhibition had only a modest effect on Cl -secretion by ADPKD cells, similar to human bronchial epithelial cells. 43 These findings point to PDE4 as the principal isoform controlling the cAMP pool involved in Cl --dependent fluid secretion by ADPKD cells.…”

Section: Discussioncontrasting

confidence: 58%

Phosphodiesterase Isoform Regulation of Cell Proliferation and Fluid Secretion in Autosomal Dominant Polycystic Kidney Disease

Pinto¹,

Raman²,

Reif³

et al. 2016

Journal of the American Society of Nephrology

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cAMP stimulates cell proliferation and Cl--dependent fluid secretion, promoting the progressive enlargement of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Intracellular cAMP levels are determined by the balance of cAMP synthesis by adenylyl cyclases and degradation by phosphodiesterases (PDEs). Therefore, PDE isoform expression and activity strongly influence global and compartmentalized cAMP levels. We report here that PDE3 and PDE4 expression levels are lower in human ADPKD tissue and cells compared with those of normal human kidneys (NHKs), whereas PDE1 levels are not significantly different. Inhibition of PDE4 caused a greater increase in basal and vasopressin (AVP)-stimulated cAMP levels and Cl -secretion by ADPKD cells than inhibition of PDE1, and inhibition of PDE4 induced cyst-like dilations in cultured mouse Pkd1 2/2 embryonic kidneys. In contrast, inhibition of PDE1 caused greater stimulation of extracellular signal-regulated kinase (ERK) and proliferation of ADPKD cells than inhibition of PDE4, and inhibition of PDE1 enhanced AVP-induced ERK activation. Notably, inhibition of PDE1, the only family of Ca 2+-regulated PDEs, also induced a mitogenic response to AVP in NHK cells, similar to the effect of restricting intracellular Ca 2+. PDE1 coimmunoprecipitated with B-Raf and A-kinase anchoring protein 79, and AVP increased this interaction in ADPKD but not NHK cells. These data suggest that whereas PDE4 is the major PDE isoform involved in the regulation of global intracellular cAMP and Cl -secretion, PDE1 specifically affects the cAMP signal to the B-Raf/MEK/ERK pathway and regulates AVP-induced proliferation of ADPKD cells.

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Section: Discussioncontrasting

confidence: 58%

Phosphodiesterase Isoform Regulation of Cell Proliferation and Fluid Secretion in Autosomal Dominant Polycystic Kidney Disease

Pinto¹,

Raman²,

Reif³

et al. 2016

Journal of the American Society of Nephrology

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“…PDEs have been shown to play a key role in the spatial control of cAMP-PKA signalling in a number of cell systems, including airway epithelial cells, where both PDE3 (Penmatsa et al, 2010) and PDE4 have been suggested to contribute to the local modulation of cAMP levels that control CFTR activity (Barnes et al, 2005). Although PDE activity has been shown to be sufficient to restrict cAMP diffusion to defined subcellular compartments in certain cell types (Oliveira et al, 2010;Terrin et al, 2006), it has been argued that the densely packed subcortical cytoskeleton might constitute an efficient barrier to cAMP diffusion and promote compartmentalized cAMP and PKA signals by allowing cAMP to accumulate locally to a level sufficient to activate PKA, while preventing activation of PKA in the bulk cytosol (Rich et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

CFTR regulation in human airway epithelial cells requires integrity of the actin cytoskeleton and compartmentalized cAMP and PKA activity

Monterisi

Favia

Guerra

et al. 2012

Journal of Cell Science

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SummaryThe cystic fibrosis transmembrane conductance regulator (CFTR) mutation DF508CFTR still causes regulatory defects when rescued to the apical membrane, suggesting that the intracellular milieu might affect its ability to respond to cAMP regulation. We recently reported that overexpression of the Na + /H + exchanger regulatory factor NHERF1 in the cystic fibrosis (CF) airway cell line CFBE41o-rescues the functional expression of DF508CFTR by promoting F-actin organization and formation of the NHERF1-ezrin-actin complex. Here, using real-time FRET reporters of both PKA activity and cAMP levels, we find that lack of an organized subcortical cytoskeleton in CFBE41o-cells causes both defective accumulation of cAMP in the subcortical compartment and excessive cytosolic accumulation of cAMP. This results in reduced subcortical levels and increased cytosolic levels of PKA activity. NHERF1 overexpression in CFBE41o-cells restores chloride secretion, subcortical cAMP compartmentalization and local PKA activity, indicating that regulation of DF508CFTR function requires not only stable expression of the mutant CFTR at the cell surface but also depends on both generation of local cAMP signals of adequate amplitude and activation of PKA in proximity of its target. Moreover, we found that the knockdown of wild-type CFTR in the non-CF 16HBE14o-cells results in both altered cytoskeletal organization and loss of cAMP compartmentalization, whereas stable overexpression of wt CFTR in CF cells restores cytoskeleton organization and reestablishes the compartmentalization of cAMP at the plasma membrane. This suggests that the presence of CFTR on the plasma membrane influences the cytoskeletal organizational state and, consequently, cAMP distribution. Our data show that a sufficiently high concentration of cAMP in the subcortical compartment is required to achieve PKA-mediated regulation of CFTR activity.

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“…Therefore, we reasoned that MAST205 may be involved in biosynthesis or intracellular trafficking of CFTR. To test whether MAST205 participates in CFTR trafficking, we measured the CFTR cell surface expression upon transfection with MAST205 by using a surface labeling assay (30). We observed that overexpression of MAST205 increased the cell surface pool of CFTR protein by at least 20% (Fig.…”

Section: Cftr Interacts With Mast205-mentioning

confidence: 97%

“…Surface Labeling Assay-The expression of CFTR at the plasma membrane was determined by using surface labeling assay (30). Briefly, the transfected cells were fixed with 3.7% formaldehyde for 10 min, blocked with 1% BSA for 30 min, and treated with ␣-FLAG-HRP for 90 min.…”

Section: Real-time Rt-pcr Analysis Of Cftr Mrna Level Uponmentioning

confidence: 99%

MAST205 Competes with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-associated Ligand for Binding to CFTR to Regulate CFTR-mediated Fluid Transport

Ren

Zhang

Yarlagadda

et al. 2013

Journal of Biological Chemistry

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Compartmentalized Cyclic Adenosine 3′,5′-Monophosphate at the Plasma Membrane Clusters PDE3A and Cystic Fibrosis Transmembrane Conductance Regulator into Microdomains

Cited by 63 publications

References 67 publications

Phosphodiesterase Isoform Regulation of Cell Proliferation and Fluid Secretion in Autosomal Dominant Polycystic Kidney Disease

Phosphodiesterase Isoform Regulation of Cell Proliferation and Fluid Secretion in Autosomal Dominant Polycystic Kidney Disease

CFTR regulation in human airway epithelial cells requires integrity of the actin cytoskeleton and compartmentalized cAMP and PKA activity

MAST205 Competes with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-associated Ligand for Binding to CFTR to Regulate CFTR-mediated Fluid Transport

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