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

Stefan, Eduard; Wiesner, Burkhard; Baillie, George S.; Mollajew, Rustam; Henn, Volker; Lorenz, Dorothea; Furkert, Jens; Santamaria, Katja; Nedvetsky, Pavel I.; Hundsrucker, Christian; Beyermann, Michael; Krause, Eberhard; Pohl, Peter; Gall, Irene; Macintyre, Andrew N.; Bachmann, S.; Houslay, Miles D.; Rosenthal, Walter; Klussmann, Enno

doi:10.1681/asn.2006020132

Cited by 134 publications

(138 citation statements)

References 47 publications

(70 reference statements)

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“…Western blotting was performed as described. 20 In brief, blocking was carried out using 1% BSA in Tris-buffered saline-Tween-20 with antibodies directed against AQP2 (C-17, Santa Cruz; goat polyclonal IgG; dilution 1:1000) and AQP2 (phospho-S261; rabbit polyclonal antibody; Santa Cruz; dilution 1:750). The specificity of the AQP2 C-17 and phospho-S261 antibodies was confirmed by loading 3.75 g per lane of the indicated peptides (WT, pS256, pS261, pS264; data not shown).…”

Section: Detection Of Ubiquitinated Aqp2mentioning

confidence: 99%

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Nedvetsky

Tabor

Tamma

et al. 2010

Journal of the American Society of Nephrology

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106

129

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Arginine-vasopressin (AVP) modulates the water channel aquaporin-2 (AQP2) in the renal collecting duct to maintain homeostasis of body water. AVP binds to vasopressin V2 receptors (V2R), increasing cAMP, which promotes the redistribution of AQP2 from intracellular vesicles into the plasma membrane. cAMP also increases AQP2 transcription, but whether altered degradation also modulates AQP2 protein levels is not well understood. Here, elevation of cAMP increased AQP2 protein levels within 30 minutes in primary inner medullary collecting duct (IMCD) cells, in human embryonic kidney (HEK) 293 cells ectopically expressing AQP2, and in mouse kidneys. Accelerated transcription or translation did not explain this increase in AQP2 abundance. In IMCD cells, cAMP inhibited p38-mitogen-activated protein kinase (p38-MAPK) via activation of protein kinase A (PKA). Inhibition of p38-MAPK associated with decreased phosphorylation (serine 261) and polyubiquitination of AQP2, preventing proteasomal degradation. Our results demonstrate that AVP enhances AQP2 protein abundance by altering its proteasomal degradation through a PKA-and p38-MAPK-dependent pathway. Aquaporin-2 (AQP2) is the water channel mediating arginine-vasopressin (AVP)-increases in water re-absorption in renal collecting duct principal cells. 1-4 AVP binds to plasma membrane-located vasopressin V2 receptors, thereby stimulating adenylyl cyclase and elevating cAMP. cAMP activates protein kinase A (PKA), which phosphorylates AQP2 at serine 256 (S256), inducing its redistribution from intracellular vesicles into the plasma membrane. 3,4 This short-term regulation of AQP2 occurs within seconds to minutes. In the case of long-term regulation, cAMP enhances AQP2 mRNA expression, followed by a rise in the AQP2 protein level within hours. 5,6 AQP2 can be degraded in proteasomes and lysosomes. 7,8 Ubiquitination directs proteins for degradation to both compartments. Monoubiquitination (mUb) is a signal for degradation in lysosomes, whereas polyubiquitination (pUb) is mainly linked to proteasomal degradation. 9 mUb of AQP2 is induced by FSK stimulation and occurs at the apical plasma membrane. 10 In WT5 cells, a model for AQP2 regulation, increased mUb of AQP2 persists

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Section: Detection Of Ubiquitinated Aqp2mentioning

confidence: 99%

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Nedvetsky

Tabor

Tamma

et al. 2010

Journal of the American Society of Nephrology

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106

129

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“…These previous experiments were carried out using AKAP-450 fragments that, by disrupting the conformation of the full protein, could destabilize PDE4D3 interactions with other sites on the AKAP. The existence of several binding sites between a PDE4D isoform and its target protein has already been reported, namely for the binding of PDE4D3 to AKAP-18 (10) and for the binding of PDE4D5 to ␤-arrestin and also to RACK1 (40 -42). Our findings suggest that PDE4D3 also has multiple binding sites on AKAP-450, at least one located within the sequence of AKAP-9 (this study) and at least one located downstream of this sequence (13).…”

Section: Discussionmentioning

confidence: 97%

The Cardiac IKs Potassium Channel Macromolecular Complex Includes the Phosphodiesterase PDE4D3

Terrenoire

Houslay

Baillie

et al. 2009

Journal of Biological Chemistry

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122

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The cardiac I Ks potassium channel is a macromolecular complex consisting of ␣-(KCNQ1) and ␤-subunits (KCNE1) and the A kinase-anchoring protein (AKAP) Yotiao (AKAP-9), which recruits protein kinase A) and protein phosphatase 1 to the channel. Here, we have tested the hypothesis that specific cAMP phosphodiesterase (PDE) isoforms of the PDE4D family that are expressed in the heart are also part of the I Ks signaling complex and contribute to its regulation by cAMP. PDE4D isoforms coimmunoprecipitated with I Ks channels in hearts of mice expressing the I Ks channel. In myocytes isolated from these mice, I Ks was increased by pharmacological PDE inhibition. PDE4D3, but not PDE4D5, co-immunoprecipitated with the I Ks channel only in Chinese hamster ovary cells co-expressing AKAP-9, and PDE4D3, but not PDE4D5, co-immunoprecipitated with AKAP-9. Functional experiments in Chinese hamster ovary cells expressing AKAP-9 and either PDE4D3 or PDE4D5 isoforms revealed modulation of the I Ks response to cAMP by PDE4D3 but not PDE4D5. We conclude that PDE4D3, like protein kinase A and protein phosphatase 1, is recruited to the I Ks channel via AKAP-9 and contributes to its critical regulation by cAMP.

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“…and hydrolyses cAMP to basal levels and resets the system, i.e. PKA becomes inactivated and AQP2 is endocytosed [28][29][30].…”

Section: The Pde4 Family Of Phosphodiesterasesmentioning

confidence: 99%

“…For example, the interaction of p75NTR and PDE4A5 [31], of AKAP18δ with PDE4D3 [28] and that of MEK1…”

Section: Peptide Spot Arrays For Mapping Protein-protein Interactionsmentioning

confidence: 99%

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

Cited by 134 publications

References 47 publications

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

Reciprocal Regulation of Aquaporin-2 Abundance and Degradation by Protein Kinase A and p38-MAP Kinase

The Cardiac IKs Potassium Channel Macromolecular Complex Includes the Phosphodiesterase PDE4D3

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

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