Activation of PDE10 and PDE11 Phosphodiesterases

Koesling

Journal of Biological Chemistry

2015

Self Cite

Background:In striatum, cortical glutamatergic and midbrain dopaminergic inputs are integrated via cAMP. Results: PDE10A, the major cAMP-hydrolyzing enzyme in striatum, is targeted into a signaling complex containing the scaffolding proteins AKAP150, PSD95, and the NMDA receptor and released upon phosphorylation. Conclusion: Targeting of PDE10 is under control of cAMP/PKA activity. Significance: Phosphorylation-dependent release of PDE10 gives rise to a feed forward mechanism.

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Phosphodiesterase 10A Is Tethered to a Synaptic Signaling Complex in Striatum

Koesling

Journal of Biological Chemistry

2015

Self Cite

“…Future work will include pathway-specific characterization of PDE10A inhibitors. Other mechanisms, such as regulation of PDE10A activity by its GAFb domain, PDE10A localization through palmitoylation, and unknown regulation through binding partners of PDE10A (Charych et al, 2010;Jäger et al, 2012;Russwurm et al, 2015), are worth evaluating.…”

Section: Study Limitationsmentioning

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

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.

Non-Canonical Cyclic Nucleotides

“…Adapted from Beste and Seifert (2013) of catalytic activity in PDE10 is characterized by two uncommon features. First, the PDE10 GAF domain tandem binds cAMP with higher affinity than cGMP (Jäger et al 2012), which indicates that GAF domains are not necessarily cGMP-specific. Second, although cAMP binding to PDE10 GAF-B enhances catalytic activity for cGMP hydrolysis at low concentrations, cAMP concentrations higher than 0.1 μM completely inhibit cGMP hydrolysis (Jäger et al 2012).…”

Section: Traditional Classification Of Pdesmentioning

confidence: 99%

Inactivation of Non-canonical Cyclic Nucleotides: Hydrolysis and Transport

Schneider

Seifert

2016

This chapter addresses cNMP hydrolysis by phosphodiesterases (PDEs) and export by multidrug resistance associated proteins (MRPs). Both mechanisms are well-established for the canonical cNMPs, cAMP, and cGMP. Increasing evidence shows that non-canonical cNMPs (specifically cCMP, cUMP) are also PDE and MRP substrates. Hydrolysis of cUMP is achieved by PDE 3A, 3B, and 9A, which possibly explains the cUMP-degrading activities previously reported for heart, adipose tissue, and brain. Regarding cCMP, the only known "conventional" (class I) PDE that hydrolyzes cCMP is PDE7A. Older reports describe cCMP-degrading PDE-like activities in mammalian tissues, bacteria, and plants, but the molecular identity of these enzymes is not clear. High K and V values, insensitivity to common inhibitors, and unusually broad substrate specificities indicate that these activities probably do not represent class I PDEs. Moreover, the older results have to be interpreted with caution, since the historical analytical methods were not as reliable as modern highly sensitive and specific techniques like HPLC-MS/MS. Besides PDEs, the transporters MRP4 and 5 are of major importance for cAMP and cGMP disposal. Additionally, both MRPs also export cUMP, while cCMP is only exported by MRP5. Much less data are available for the non-canonical cNMPs, cIMP, cXMP, and cTMP. None of these cNMPs has been examined as MRP substrate. It was shown, however, that they are hydrolyzed by several conventional class I PDEs. Finally, this chapter reveals that there are still large gaps in our knowledge about PDE and MRP activities for canonical and non-canonical cNMPs. Future research should perform a comprehensive characterization of the known PDEs and MRPs with the physiologically most important cNMP substrates.