In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting

Beard, Matthew; Huston, Elaine; Campbell, Lachlan; Gall, Irene; McPhee, Ian; Yarwood, Stephen J.; Scotland, Grant; Houslay, Miles D.

doi:10.1016/s0898-6568(01)00264-9

Cited by 46 publications

(69 citation statements)

References 66 publications

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“…Regulatory proteins, such as phosphatases (PP) 33 and the PDEs 34,35 themselves, are often included within such spatially confined signaling domains, providing a means to switch off the signal delivered by cAMP in specific locations. The notion that targeting of PDEs is important in cyclic nucleotide signaling came from work on PDE4s 36,37 ; PDE4D3 has been shown to bind several AKAPs, including muscleselective AKAP (mAKAP) in the heart. 38 An example of how the cAMP signal is transduced through a multimeric signaling domain is the activation of the L-type Ca 2ϩ channel on ␤ 2 -adrenergic receptor stimulation in hippocampal neurons.…”

Section: Spatial Control Of Cyclic Nucleotide Signalingmentioning

confidence: 99%

cAMP and cGMP Signaling Cross-Talk

Zaccolo

Movsesian²

2007

Circulation Research

316

150

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Abstract-Cyclic nucleotide phosphodiesterases regulate cAMP-mediated signaling by controlling intracellular cAMP content.The cAMP-hydrolyzing activity of several families of cyclic nucleotide phosphodiesterases found in human heart is regulated by cGMP. In the case of PDE2, this regulation primarily involves the allosteric stimulation of cAMP hydrolysis by cGMP. For PDE3, cGMP acts as a competitive inhibitor of cAMP hydrolysis. Several cGMP-mediated responses in cardiac cells, including a potentiation of Ca 2ϩ currents and a diminution of the responsiveness to ␤-adrenergic receptor agonists, have been shown to result from the effects of cGMP on cAMP hydrolysis. These effects appear to be dependent on the specific spatial distribution of the cGMP-generating and cAMP-hydrolyzing proteins, as well as on the intracellular concentrations of the two cyclic nucleotides. Gaining a more precise understanding of how these cross-talk mechanisms are individually regulated and coordinated is an important direction for future research. (Circ Res. 2007;100:1569-1578.) Key Words: phosphodiesterases Ⅲ signaling cross-talk Ⅲ cAMP Ⅲ cGMP Ⅲ compartmentalization T he second messengers cAMP and cGMP are important regulators of cardiac function. cAMP, which is generated by adenylyl cyclases (AC) on G protein-coupled receptor stimulation by catecholamines, regulates the strength and frequency of cardiac contraction and relaxation. The main downstream effector of cAMP is protein kinase A (PKA), 1 though cyclic nucleotide-gated ion channels and the exchange factor for Rap, Epac, 2 are also cAMP targets. cGMP, which is generated by guanylyl cyclases (GC) in response to nitric oxide (NO) and natriuretic peptides, modulates inotropy and metabolic responses 3 via the activation of its downstream effectors, protein kinase G (PKG) and cyclic nucleotide-gated channels. These two signaling pathways often exert opposing influences on cardiac function, 3 in part as a consequence of the opposing effects of PKA-and PKG-mediated phosphorylation on target proteins.A separate level of cross-talk between the cAMP and cGMP signaling pathways involves the activity of the cyclic nucleotide-degrading enzymes, phosphodiesterases (PDEs). In the heart, cGMP acts as a regulator of the activity of cAMPhydrolyzing PDEs, such that the intracellular concentration of cGMP can influence the intracellular concentration of cAMP.Original received November 11, 2006; revision received March 20, 2007; accepted March 27, 2007. From the Dulbecco Telethon Institute at the Venetian Institute of Molecular Medicine (M.Z.), Padova, Italy; and the Cardiology Section, Veterans Affairs Salt Lake City Health Care System (M.A.M.), and Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah.Correspondence The modulatory effects of cGMP on cAMP-hydrolyzing PDEs occur at nanomolar to micromolar concentrations of cGMP. This concentration range is comparable to that at which cGMP activates canonical targets such as PKG (K ...

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Section: Spatial Control Of Cyclic Nucleotide Signalingmentioning

confidence: 99%

cAMP and cGMP Signaling Cross-Talk

Zaccolo

Movsesian²

2007

Circulation Research

316

150

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“…According to their structures, each subtype is classified as super-short, short, and long isoforms (Houslay and Adams, 2003). Long-form PDE4 is known to be targeted to membrane fractions or interact with its partner molecules, such as anchoring proteins (Shakur et al, 1993;Beard et al, 2002;Bolger et al, 2003;Conti et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

AnAplysiaType 4 Phosphodiesterase Homolog Localizes at the Presynaptic Terminals ofAplysiaNeuron and Regulates Synaptic Facilitation

Park

Lee²,

Lee³

et al. 2005

J. Neurosci.

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The cAMP-dependent signaling pathway is critically involved in memory-related synaptic plasticity. cAMP-specific type 4 phosphodiesterases (PDE4) play a role in this process by regulating the cAMP concentration. However, it is unclear how PDE4 is involved in regulating synaptic plasticity. To address this issue in Aplysia sensory-to-motor synapses, we identified a long isoform of the PDE4 homolog in Aplysia kurodai (apPDE), with genetic and biochemical properties similar to those of mammalian PDE4s. Furthermore, apPDE is localized to the membrane and presynaptic region. Both apPDE overexpression and knock-down impaired short-and long-term facilitation, indicating that an appropriate expression level of apPDE in synaptic regions is required for normal synaptic facilitation. By using fluorescence resonance energy transfer-based measurement of in vivo protein kinase A (PKA) activation, we found that the PKA activation by 5-hydroxytryptamine (5-HT) was impaired in both apPDE-overexpressed and knock-down synapses. Analogous to the inhibition of apPDE by RNA interference, chronic rolipram treatment before 5-HT stimulation also impaired the PKA activation by 5-HT, suggesting that regulation of the synaptic cAMP level by PDE4 is critical for normal synaptic facilitation. Together, we suggest that PDE4s localized in the synapses play a critical role in regulating the optimum cAMP level required for normal synaptic plasticity.

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“…PDE4A4/5 is expressed in a wide variety of tissues, including the pituitary (Mackenzie et al 2008, Lennox et al 2011, and both membrane and cytosolic localisation has been detected (Huston et al 2000). PDE4A5 was demonstrated to interact with the SH3 domains of SRC family tyrosyl kinases (O'Connell et al 1996, Beard et al 2002, with AKAP3 (Bajpai et al 2006) and with AIP (Bolger et al 2003). AIP was initially identified as a direct binding partner of PDE4A5 by a Y2H screening of a rat brain cDNA library.…”

Section: Pde4a5mentioning

confidence: 99%

AIP and its interacting partners

Trivellin¹,

Korbonits²

2011

Journal of Endocrinology

130

119

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Germline mutations in the aryl hydrocarbon receptorinteracting protein gene (AIP) predispose to young-onset pituitary tumours, most often to GH-or prolactin-secreting adenomas, and most of these patients belong to familial isolated pituitary adenoma families. The molecular pathway initiated by the loss-of-function AIP mutations leading to pituitary tumour formation is unknown. AIP, a co-chaperone of heat-shock protein 90 and various nuclear receptors, belongs to the family of tetratricopeptide repeat (TPR)-containing proteins. It has three antiparallel a-helix motifs (TPR domains) that mediate the interaction of AIP with most of its partners. In this review, we summarise the known interactions of AIP described so far. The identification of AIP partners and the understanding of how AIP interacts with these proteins might help to explain the specific phenotype of the families with heterozygous AIP mutations, to gain deeper insight into the pathological process of pituitary tumour formation and to identify novel drug targets.

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In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting

Cited by 46 publications

References 66 publications

cAMP and cGMP Signaling Cross-Talk

cAMP and cGMP Signaling Cross-Talk

AnAplysiaType 4 Phosphodiesterase Homolog Localizes at the Presynaptic Terminals ofAplysiaNeuron and Regulates Synaptic Facilitation

AIP and its interacting partners

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