In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region

McCahill, Angela; McSorley, Theresa; Huston, Elaine; Hill, E.; Lynch, Martin J.; Gall, Irene; Keryer, Guy; Lygren, Birgitte; Taskén, Kjetil; VANHEEKE, G

doi:10.1016/j.cellsig.2005.04.003

Cited by 102 publications

(105 citation statements)

References 66 publications

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“…PDE4D3 can interact with mAKAP and AKAP450 (13,14,40), but mAKAP is not expressed in IMCD cells, whereas AKAP450 is not detectable on AQP2-bearing vesicles (data not shown). Given the predisposition of PDE4D3 to bind to AKAP, we investigated whether PDE4D3 forms complexes with AKAP18.…”

Section: Akap18␦ Is An Anchor For Pde4dmentioning

confidence: 93%

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

133

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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: Akap18␦ Is An Anchor For Pde4dmentioning

confidence: 93%

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

133

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“…In rat Sertoli cells, AKAP9 coordinates PKA and phosphodiesterase 4D3 (Tasken et al 2001). Large isoforms of AKAP9 are associated with centrosomal function and signaling, microtubule organization, and nucleation at the cis-Golgi (Sillibourne et al 2002;Takahashi et al 2002;Keryer et al 2003a;McCahill et al 2005;Rivero et al 2009). To date, no functional role has been described for AKAP9 in spermatogenesis.…”

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confidence: 99%

AKAP9 Is Essential for Spermatogenesis and Sertoli Cell Maturation in Mice

et al. 2013

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Mammalian male fertility relies on complex inter-and intracellular signaling during spermatogenesis. Here we describe three alleles of the widely expressed A-kinase anchoring protein 9 (Akap9) gene, all of which cause gametogenic failure and infertility in the absence of marked somatic phenotypes. Akap9 disruption does not affect spindle nucleation or progression of prophase I of meiosis but does inhibit maturation of Sertoli cells, which continue to express the immaturity markers anti-Mullerian hormone and thyroid hormone receptor alpha in adults and fail to express the maturation marker p27 Kip1 . Furthermore, gap and tight junctions essential for blood-testis barrier (BTB) organization are disrupted. Connexin43 (Cx43) and zona occludens-1 are improperly localized in Akap9 mutant testes, and Cx43 fails to compartmentalize germ cells near the BTB. These results identify and support a novel reproductive tissue-specific role for Akap9 in the coordinated regulation of Sertoli cells in the testis.

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“…This is associated with an activation of ERK1/2 and thus caused by a local rise in cAMP, PKA activation and G protein switching from G s to G i (see 2.2) [33]. The dominant negative approach has for example also elucidated that PDE4D3 controls a cAMP microdomain at the β 1 -adrenoceptor in cardiac myocytes [50] and that PDE4D3 and PDE4C2 control AKAP-anchored PKA activity in the perinuclear region [51]. The dominant negative approach can reveal relevant physiological mechanisms, and contribute to validate a target.…”

Section: Pde4 Isozymes' Protein-protein Interactions As Drug Targets mentioning

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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In resting COS1 cells a dominant negative approach shows that specific, anchored PDE4 cAMP phosphodiesterase isoforms gate the activation, by basal cyclic AMP production, of AKAP-tethered protein kinase A type II located in the centrosomal region

Cited by 102 publications

References 66 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

AKAP9 Is Essential for Spermatogenesis and Sertoli Cell Maturation in Mice

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

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