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

• The mouse PDE10A mRNA is expressed through alternative splicing and polyadenylation in a tissue-specific manner and that transcription of striatal PDE10A mRNA is driven by two promoters [5].
• The PDE10A gene spanned > 200 kb and contained 24 exons [6].
• However, other GAF-PDEs, PDE2A and PDE10A, displayed different exon organization from PDE11A although these three PDEs are similar in their amino-acid sequences to each other [7].

Anatomical context of PDE10A

• Immuno-electron microscopy of striatum confirms that PDE10A is most often associated with membranes in dendrites and spines [8].
• In order to investigate the physiological role of PDE10A in the central nervous system, PDE10A knockout mice (PDE10A(-/-)) were characterized both behaviorally and neurochemically [9].
• We find by confocal microscopy that PDE10A-like immunoreactivity is excluded from each class of striatal interneuron [8].
• PDE10A transcripts were abundant in the brain and testis [10].
• Outside the brain, PDE10A immunoreactivity is less intense, and distribution is limited to few tissues such as the testis, epididymal sperm, and enteric ganglia [11].

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

• In situ hybridization analysis using a PDE10A riboprobe demonstrated the presence of PDE10A transcripts in the neurons of the striatum and the olfactory tubercle regions of the brain [10].

References