Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP/PKA Signaling in the Striatum

Nishi, Akinori; Kuroiwa, Mahomi; Miller, Diane B.; O’Callaghan, James P.; Bateup, Helen S.; Shuto, Takahide; Sotogaku, Naoki; Fukuda, Takahiro; Heintz, Nathaniel; Greengard, Paul; Snyder, Gretchen L.

doi:10.1523/jneurosci.2518-08.2008

Cited by 253 publications

(260 citation statements)

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“…Although our data show a clear role for PDE4 in GluA1 phosphorylation and membrane insertion, it is likely that there are other PDE families that have yet to be implicated in the regulation of GluA1 S845 phosphorylation and AMPAR trafficking. An additional player may be PDE10, which also regulates GluA1 S845 phosphorylation in vivo (36); however, the effect of PDE10 inhibition on AMPAR membrane insertion has yet to be explored. Our data suggest that PDE4 is not the only ERK substrate that modulates AMPAR trafficking.…”

Section: Discussionmentioning

confidence: 99%

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

Song

Massenburg

Wenderski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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AMPA-type glutamate receptor (AMPAR) trafficking is essential for modulating synaptic transmission strength. Prior studies that have characterized signaling pathways underlying AMPAR trafficking have identified the cAMP/PKA-mediated phosphorylation of GluA1, an AMPAR subunit, as a key step in the membrane insertion of AMPAR. Inhibition of ERK impairs AMPAR membrane insertion, but the mechanism by which ERK exerts its effect is unknown. Dopamine, an activator of both PKA and ERK, induces AMPAR insertion, but the relationship between the two protein kinases in the process is not understood. We used a combination of computational modeling and live cell imaging to determine the relationship between ERK and PKA in AMPAR insertion. We developed a dynamical model to study the effects of phosphodiesterase 4 (PDE4), a cAMP phosphodiesterase that is phosphorylated and inhibited by ERK, on the membrane insertion of AMPAR. The model predicted that PKA could be a downstream effector of ERK in regulating AMPAR insertion. We experimentally tested the model predictions and found that dopamine-induced ERK phosphorylates and inhibits PDE4. This regulation results in increased cAMP levels and PKA-mediated phosphorylation of DARPP-32 and GluA1, leading to increased GluA1 trafficking to the membrane. These findings provide unique insight into an unanticipated network topology in which ERK uses PDE4 to regulate PKA output during dopamine signaling. The combination of dynamical models and experiments has helped us unravel the complex interactions between two protein kinase pathways in regulating a fundamental molecular process underlying synaptic plasticity.T he strength of synaptic transmission depends on the number of AMPA-type glutamate receptors (AMPARs) localized to the synaptic membrane. The regulated trafficking of AMPARs in and out of the postsynaptic membrane controls the number of synaptic AMPARs and is thought to underlie synaptic plasticity (1). AMPARs are composed of four subunits (GluA1-4), which assemble as homo-or hetero-tetramers to mediate excitatory transmissions in the brain. There are a number of intracellular pathways that regulate signal-initiated trafficking of GluA1-containing AMPARs. For instance, PKA and PKG, the cyclic nucleotide-activated kinases, phosphorylate GluA1 at S845 (2, 3). Phosphorylation of S845 is required for GluA1 synaptic insertion because mutation to A845 prevents GluA1 exocytosis (4). Dopamine, a modulatory neurotransmitter that increases cAMP/ PKA levels, promotes GluA1 phosphorylation at S845 and AMPAR insertion into the plasma membrane (3, 5, 6). Additional signaling pathways influence this process, but the role they play in dopamine-mediated AMPAR trafficking is not known. ERK, a downstream effector of dopamine, promotes AMPAR membrane insertion even though ERK does not directly phosphorylate GluA1 (7,8). The objective of this study was to identify the mechanism by which ERK regulates dopamine-mediated GluA1 membrane insertion. Based on our observation that ERK inhibition decreases dop...

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Section: Discussionmentioning

confidence: 99%

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

Song

Massenburg

Wenderski

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This role in striatal signaling has made PDE10A an enzyme of particular interest because it is likely involved in several neuropsychiatric disorders. This hypothesis is supported by preclinical studies with PDE10A inhibitors, showing that pharmacologic inhibition of PDE10A leads to activation of medium spiny neurons (MSNs) and alteration of behavioral aspects modulated by the striatal circuit (6). Disruption of the conditioned avoidance response, an established preclinical model for antipsychotic activity, was observed after the administration of PDE10A inhibitor TP-10 (7) and MP-10 (8), and reduced exploratory locomotor activity was seen (7).…”

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confidence: 91%

Quantification of ¹⁸F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain

et al. 2013

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Phosphodiesterase 10A (PDE10A) plays a central role in striatal signaling and is implicated in several neuropsychiatric disorders, such as movement disorders and schizophrenia. We performed initial brain kinetic modeling of the novel PDE10A tracer 18 F-JNJ-42259152 (2-[[4-[1-(2-18 F-fluoroethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]-3,5-dimethyl-pyridine) and studied test-retest reproducibility in healthy volunteers. Methods: Twelve healthy volunteers (5 men, 7 women; age range, 42-77 y) were scanned dynamically up to 135 min after bolus injection of 172.5 6 10.3 MBq of 18 F-JNJ42259152. Four volunteers (2 men, 2 women) underwent retest scanning, with a mean interscan interval of 37 d. Input functions and tracer parent fractions were determined using arterial sampling and high-performance liquid chromatography analysis. Volumes of interest for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were delineated using individual volumetric T1 MR imaging scans. Onetissue (1T) and 2-tissue (2T) models were evaluated to calculate total distribution volume (V T ). Simplified models were also tested to calculate binding potential (BP ND ), including the simplified reference tissue model (SRTM) and multilinear reference tissue model, using the frontal cortex as the optimal reference tissue. The stability of V T and BP ND was assessed down to a 60-min scan time. Results: The average intact tracer half-life in blood was 90 min. The 2T model V T values for the putamen, caudate nucleus, ventral striatum, substantia nigra, thalamus, frontal cortex, and cerebellum were 1.54 6 0.37, 0.90 6 0.24, 0.64 6 0.18, 0.42 6 0.09, 0.35 6 0.09, 0.30 6 0.07, and 0.36 6 0.12, respectively. The 1T model provided significantly lower V T values, which were well correlated to the 2T V T . SRTM BP ND values referenced to the frontal cortex were 3.45 6 0.43, 1.78 6 0.35, 1.10 6 0.31, and 0.44 6 0.09 for the respective target regions putamen, caudate nucleus, ventral striatum, and substantia nigra, with similar values for the multilinear reference tissue model. Good correlations were found for the target regions putamen, caudate nucleus, ventral striatum, and substantia nigra between the 2T-compartment model BP ND and the SRTM BP ND (r 5 0.57, 0.82, 0.70, and 0.64, respectively). SRTM BP ND using a 90-and 60-min acquisition interval showed low bias. Test-retest variability was 5%-19% for 2T V T and 5%-12% for BP ND SRTM. Conclusion: Kinetic modeling of 18 F-JNJ-42259152 shows that PDE10A activity can be reliably quantified and simplified using a reference tissue model with the frontal cortex as reference and a 60-min acquisition period.Key Words: PDE10A; PET; radioligand; 18 F; phosphodiesterase J Nucl Med 2013; 54:1285 54: -1293 54: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is a dual-substrate enzyme with a restricted distribution, predominantly in the human brain in medium spiny neurons of the striatum, the substantia nigra, the nucleus accumbens and olfactory tuberculum (1)...

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“…Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both cAMP and cyclic GMP (cGMP), and is selectively expressed in MSNs (Nishi et al, 2008;Sano et al, 2008;Xie et al, 2006). Given the high level of expression of PDE10A in MSNs, PDE10A inhibitors are thought to increase cyclic nucleotide levels and activate downstream signal transduction in the striatum, similar to D 2 antagonists in indirect pathway neurons.…”

Section: Introductionmentioning

confidence: 99%

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Suzuki

Harada

Suzuki

et al. 2016

Neuropsychopharmacol

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Phosphodiesterase 10A (PDE10A) inhibitors are expected to be novel drugs for schizophrenia through activation of both direct and indirect pathway medium spiny neurons. However, excess activation of the direct pathway by a dopamine D 1 receptor agonist SKF82958 canceled antipsychotic-like effects of a dopamine D 2 receptor antagonist haloperidol in methamphetamine (METH)-induced hyperactivity in rats. Thus, balanced activation of these pathways may be critical for PDE10A inhibitors. Current antipsychotics and the novel PDE10A inhibitor TAK-063, but not the selective PDE10A inhibitor MP-10, produced dose-dependent antipsychotic-like effects in METH-induced hyperactivity and prepulse inhibition in rodents. TAK-063 and MP-10 activated the indirect pathway to a similar extent; however, MP-10 caused greater activation of the direct pathway than did TAK-063. Interestingly, the off-rate of TAK-063 from PDE10A in rat brain sections was faster than that of MP-10, and a slower off-rate PDE10A inhibitor with TAK-063-like chemical structure showed an MP-10-like pharmacological profile. In general, faster off-rate enzyme inhibitors are more sensitive than slower off-rate inhibitors to binding inhibition by enzyme substrates. As expected, TAK-063 was more sensitive than MP-10 to binding inhibition by cyclic nucleotides. Moreover, an immunohistochemistry study suggested that cyclic adenosine monophosphate levels in the direct pathway were higher than those in the indirect pathway. These data can explain why TAK-063 showed partial activation of the direct pathway compared with MP-10. The findings presented here suggest that TAK-063's antipsychotic-like efficacy may be attributable to its unique pharmacological properties, resulting in balanced activation of the direct and indirect striatal pathways.

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Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP/PKA Signaling in the Striatum

Cited by 253 publications

References 48 publications

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

Quantification of ¹⁸F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

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Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP/PKA Signaling in the Striatum

Cited by 253 publications

References 48 publications

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

Quantification of 18F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain

TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms

Contact Info

Product

Resources

About

Quantification of ¹⁸F-JNJ-42259152, a Novel Phosphodiesterase 10A PET Tracer: Kinetic Modeling and Test–Retest Study in Human Brain