Improving Memory: A Role for Phosphodiesterases

Blokland, Arjan; Schreiber, Rudy; Prickaerts, Jos

doi:10.2174/138161206777698855

Cited by 159 publications

(102 citation statements)

References 103 publications

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“…cAMP and the control of its degradation by PDEs, including PDE4, has a well appreciated role in regulating learning and memory processes (Barad et al, 1998;O'Donnell and Zhang, 2004;Arnsten et al, 2005;Blokland et al, 2006). Recently, we have shown that DISC1 interacts with PDE4B (Millar et al, 2005;Cheung et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

Murdoch¹,

Mackie²,

Collins³

et al. 2007

J. Neurosci.

145

164

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Disrupted-in-schizophrenia 1 (DISC1) is a genetic susceptibility factor for schizophrenia and related severe psychiatric conditions. DISC1 is a multifunctional scaffold protein that is able to interact with several proteins, including the independently identified schizophrenia risk factor phosphodiesterase-4B (PDE4B). Here we report that the 100 kDa full-length DISC1 isoform (fl-DISC1) can bind members of each of the four gene, cAMP-specific PDE4 family. Elevation of intracellular cAMP levels, so as to activate protein kinase A, caused the release of PDE4D3 and PDE4C2 isoforms from fl-DISC1 while not affecting binding of PDE4B1 and PDE4A5 isoforms. Using a peptide array strategy, we show that PDE4D3 binds fl-DISC1 through two regions found in common with PDE4B isoforms, the interaction of which is supplemented because of the presence of additional PDE4B-specific binding sites. We propose that the additional binding sites found in PDE4B1 underpin its resistance to release during cAMP elevation. We identify, for the first time, a functional distinction between the 100 kDa long DISC1 isoform and the short 71 kDa isoform. Thus, changes in the expression pattern of DISC1 and PDE4 isoforms offers a means to reprogram their interaction and to determine whether the PDE4 sequestered by DISC1 is released after cAMP elevation. The PDE4B-specific binding sites encompass point mutations in mouse Disc1 that confer phenotypes related to schizophrenia and depression and that affect binding to PDE4B. Thus, genetic variation in DISC1 and PDE4 that influence either isoform expression or docking site functioning may directly affect psychopathology.

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Section: Discussionmentioning

confidence: 99%

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

Murdoch¹,

Mackie²,

Collins³

et al. 2007

J. Neurosci.

145

164

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“…1994; Blokland et al, 2006;Ghavami et al, 2006;Richter et al, 2013). Regulation of cAMP levels in brain by PDE4 modulates one of the fundamental pathways underlying synaptic plasticity, longlasting late-phase long-term potentiation, via activation of protein kinase A and cAMP response element-binding protein (Slack and Pockett, 1991;Frey et al, 1993;Matthies and Reymann, 1993).…”

Section: Introductionmentioning

confidence: 99%

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

Rutter

Poffe

Cavallini

et al. 2014

J Pharmacol Exp Ther

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Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe doselimiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo [3,4-b] pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC 50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC 50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was .150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was .10 versus ,1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.

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“…PDE4s are also related to various diseases such as asthma, chronic obstructive pulmonary disease (COPD), and depression (Houslay and Adams 2003;McCahill et al 2008). Presently, selective or broadspectrum PDE4 inhibitors have the potential to be used for treating various diseases including asthma and COPD (Spina 2008), and as antidepressants and memory-enhancing agents (Blokland et al 2006;McCahill et al 2008). …”

mentioning

confidence: 99%

N termini of apPDE4 isoforms are responsible for targeting the isoforms to different cellular membranes

Jang¹,

Park²,

Lee³

et al. 2010

Learn. Mem.

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Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the cytoplasm, plasma membrane, and both plasma membrane and presynaptic terminals, respectively. The N-terminal 20 amino acids of the long form of apPDE4 were involved in presynaptic terminal targeting by binding to several lipids. In addition, the N terminus of the short form of apPDE4 bound to several lipids including phosphoinositols, thereby targeting the plasma membrane. Overexpression of the long and the short forms, but not the supershort form attenuated 5-HT-induced membrane hyperexcitability. Finally, the knockdown of apPDE4s in sensory neurons impaired both short-term and long-term facilitation. Thus, these results suggest that apPDE4s can participate in the regulation of cAMP signaling through specific subcellular localization by means of lipid binding activities.

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Improving Memory: A Role for Phosphodiesterases

Cited by 159 publications

References 103 publications

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

GSK356278, a Potent, Selective, Brain-Penetrant Phosphodiesterase 4 Inhibitor That Demonstrates Anxiolytic and Cognition-Enhancing Effects without Inducing Side Effects in Preclinical Species

N termini of apPDE4 isoforms are responsible for targeting the isoforms to different cellular membranes

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