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Gene Review

PDE10A  -  phosphodiesterase 10A

Homo sapiens

Synonyms: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
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Psychiatry related information on PDE10A

  • In addition, by enhancing corticostriatal signaling, PDE10A inhibitors have the potential to improve some of the cognitive symptoms of schizophrenia [1].
  • In particular, PDE10A may play a role in disorders that involve striatal neurons, such as Huntington's disease and psychosis [2].

High impact information on PDE10A

  • It is hypothesized that cAMP signaling in the Golgi area and the cytosol in neurons is controlled through alteration of subcellular localization of PDE10A brought by activation of PKA in response to intracellular elevations of cAMP [3].
  • PDE10A transcripts were particularly abundant in the putamen and caudate nucleus regions of brain and in thyroid and testis, and in much lower amounts in other tissues [4].
  • The PDE10A gene was located on chromosome 6q26 by fluorescent in situ hybridization analysis [4].
  • cDNA encoding a novel phosphodiesterase (PDE) was isolated from a human fetal lung cDNA library and designated PDE10A [4].
  • Recombinant PDE10A transfected and expressed in COS-7 cells hydrolyzed cAMP and cGMP with Km values of 0.26 and 7.2 microM, respectively, and Vmax with cGMP was almost twice that with cAMP [4].

Biological context of PDE10A


Anatomical context of PDE10A


Associations of PDE10A with chemical compounds

  • Inhibitors that are selective for other PDE families are poor inhibitors of PDE10A; however, PDE10A is inhibited by the non-specific PDE inhibitor, IBMX [12].
  • A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines [13].
  • From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B [13].
  • In contrast, PDE10A(-/-) and PDE10A(+/+) mice responded similarly to the locomotor stimulating effects of amphetamine and methamphetamine [9].
  • PDE10A inhibitors reduce exploratory activity and antagonize the stimulant response to both amphetamine and N-methyl-d-aspartate antagonists such as phencyclidine [1].
  • In the PDE10A GAF-B domain, cAMP tightly binds to a cNMP-binding pocket [14].

Analytical, diagnostic and therapeutic context of PDE10A


  1. Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. Menniti, F.S., Chappie, T.A., Humphrey, J.M., Schmidt, C.J. Current opinion in investigational drugs (London, England : 2000) (2007) [Pubmed]
  2. Role of phosphodiesterases in neurological and psychiatric disease. Hebb, A.L., Robertson, H.A. Current opinion in pharmacology (2007) [Pubmed]
  3. Subcellular localization of cyclic nucleotide phosphodiesterase type 10A variants, and alteration of the localization by cAMP-dependent protein kinase-dependent phosphorylation. Kotera, J., Sasaki, T., Kobayashi, T., Fujishige, K., Yamashita, Y., Omori, K. J. Biol. Chem. (2004) [Pubmed]
  4. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). Fujishige, K., Kotera, J., Michibata, H., Yuasa, K., Takebayashi, S., Okumura, K., Omori, K. J. Biol. Chem. (1999) [Pubmed]
  5. Mutant huntingtin affects the rate of transcription of striatum-specific isoforms of phosphodiesterase 10A. Hu, H., McCaw, E.A., Hebb, A.L., Gomez, G.T., Denovan-Wright, E.M. Eur. J. Neurosci. (2004) [Pubmed]
  6. The human phosphodiesterase PDE10A gene genomic organization and evolutionary relatedness with other PDEs containing GAF domains. Fujishige, K., Kotera, J., Yuasa, K., Omori, K. Eur. J. Biochem. (2000) [Pubmed]
  7. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. Yuasa, K., Kanoh, Y., Okumura, K., Omori, K. Eur. J. Biochem. (2001) [Pubmed]
  8. Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Xie, Z., Adamowicz, W.O., Eldred, W.D., Jakowski, A.B., Kleiman, R.J., Morton, D.G., Stephenson, D.T., Strick, C.A., Williams, R.D., Menniti, F.S. Neuroscience (2006) [Pubmed]
  9. Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. Siuciak, J.A., McCarthy, S.A., Chapin, D.S., Fujiwara, R.A., James, L.C., Williams, R.D., Stock, J.L., McNeish, J.D., Strick, C.A., Menniti, F.S., Schmidt, C.J. Neuropharmacology (2006) [Pubmed]
  10. Striatum- and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Fujishige, K., Kotera, J., Omori, K. Eur. J. Biochem. (1999) [Pubmed]
  11. Immunohistochemical Localization of Phosphodiesterase 10A in Multiple Mammalian Species. Coskran, T.M., Morton, D., Menniti, F.S., Adamowicz, W.O., Kleiman, R.J., Ryan, A.M., Strick, C.A., Schmidt, C.J., Stephenson, D.T. J. Histochem. Cytochem. (2006) [Pubmed]
  12. Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase. Loughney, K., Snyder, P.B., Uher, L., Rosman, G.J., Ferguson, K., Florio, V.A. Gene (1999) [Pubmed]
  13. Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors. Chappie, T.A., Humphrey, J.M., Allen, M.P., Estep, K.G., Fox, C.B., Lebel, L.A., Liras, S., Marr, E.S., Menniti, F.S., Pandit, J., Schmidt, C.J., Tu, M., Williams, R.D., Yang, F.V. J. Med. Chem. (2007) [Pubmed]
  14. Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP. Handa, N., Mizohata, E., Kishishita, S., Toyama, M., Morita, S., Uchikubo-Kamo, T., Akasaka, R., Omori, K., Kotera, J., Terada, T., Shirouzu, M., Yokoyama, S. J. Biol. Chem. (2008) [Pubmed]
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