Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A

Soderling, Scott H.; Bayuga, Sharon J.; Beavo, Joseph A.

doi:10.1073/pnas.96.12.7071

Cited by 353 publications

(250 citation statements)

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“…These numbers suggest a dual substrate specificity of PDE10A2, although the enzyme is more effective toward cAMP. The V max values of our PDE10A2 catalytic domain are 507 nmol/min per mg for cAMP and 1,860 nmol/min per mg for cGMP and are comparable with those for the full-length PDE10A1 (10). There are two divalent metal ions at the active site of wild-type PDE10A2.…”

Section: Resultsmentioning

confidence: 59%

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Structural insight into substrate specificity of phosphodiesterase 10

Wang

Liu

Hou

et al. 2007

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

103

138

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Phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. It remains unknown how individual PDE families selectively recognize cAMP and cGMP. This work reports structural studies on substrate specificity. The crystal structures of the catalytic domains of the D674A and D564N mutants of PDE10A2 in complex with cAMP and cGMP reveal that two substrates bind to the active site with the same syn configuration but different orientations and interactions. The products AMP and GMP bind PDE10A2 with the anti configuration and interact with both divalent metals, in contrast to no direct contact of the substrates. The structures suggest that the syn configurations of cAMP and cGMP are the genuine substrates for PDE10 and the specificity is achieved through the different interactions and conformations of the substrates. The PDE10A2 structures also show that the conformation of the invariant glutamine is locked by two hydrogen bonds and is unlikely to switch for substrate recognition. Sequence alignment shows a potential pocket, in which variation of amino acids across PDE families defines the size and shape of the pocket and thus determines the substrate specificity.crystal structure ͉ cyclic nucleotides cAMP and cGMP C yclic nucleotide phosphodiesterases (PDEs) are enzymes hydrolyzing the second messengers adenosine and guanosine 3Ј,5Ј-cyclic monophosphates (cAMP and cGMP). The human genome encodes 21 PDE genes that are categorized into 11 families (1, 2). Selective inhibitors against individual PDE families have been developed as therapeutics for treatment of various human diseases (3-8). The best known examples are the PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) that have been used for treatment of male erectile dysfunction (5). Sildenafil (Revatio) has also been approved for treatment of pulmonary hypertension (9). PDE10 was independently identified by three groups in 1999 and shows a dual activity on hydrolysis of both cAMP and cGMP (10-12). PDE10 is highly expressed in brain striatum (13-16). Reduction of PDE10A mRNA and protein levels in striatum of transgenic mice implies a role of PDE10A in Huntington's disease (17,18). Knockout mice experiments suggest that PDE10A is involved in regulating striatal output, possibly by reducing the sensitivity of medium spiny neurons to glutamatergic excitation (19). The PDE10 inhibitor papaverine is effective in improving executive function deficits associated with schizophrenia, and therefore inhibition of PDE10 may represent an approach to treatment of psychosis (20,21).PDE families contain a variable N-terminal regulatory domain and a conserved C-terminal catalytic domain. Individual PDE families show different substrate preferences. Crystal structures have been reported for the catalytic domains of seven PDE families in the unliganded form or in complex with inhibitors or products: PDE1B, PDE2A, PDE3B, PDE4B/4D, PDE5A, PDE7A, and PDE9A (22-34). However, it remains a puzzle how the conserved catalytic pocket of the PDE famili...

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Section: Resultsmentioning

confidence: 59%

“…Sildenafil (Revatio) has also been approved for treatment of pulmonary hypertension (9). PDE10 was independently identified by three groups in 1999 and shows a dual activity on hydrolysis of both cAMP and cGMP (10)(11)(12). PDE10 is highly expressed in brain striatum (13)(14)(15)(16).…”

mentioning

confidence: 99%

Structural insight into substrate specificity of phosphodiesterase 10

Wang

Liu

Hou

et al. 2007

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

103

138

View full text Add to dashboard Cite

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“…We have isolated cDNAs for a dual substrate PDE that hydrolyzes both cAMP and cGMP (PDE10A) from humans and rats (10), and another group has reported mouse PDE10A cDNA (11). K m values of PDE10A for cAMP and cGMP are 0.26 M and 7.2 M, respectively, and V max values for them are slightly different (10).…”

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confidence: 99%

Subcellular Localization of Cyclic Nucleotide Phosphodiesterase Type 10A Variants, and Alteration of the Localization by cAMP-dependent Protein Kinase-dependent Phosphorylation

Kotera

Sasaki

Tamaki

et al. 2004

Journal of Biological Chemistry

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Our previous studies have suggested that two phosphodiesterase type 10A (PDE10A) variants, PDE10A1 and PDE10A2 transcripts, are mainly expressed in humans and that PDE10A2 and PDE10A3 transcripts are major variants in rats. In the present study, immunoblot analysis demonstrated that PDE10A proteins, especially PDE10A2, are more abundant in membrane fractions than in cytosolic fractions of rat striatum. Recombinant PDE10A1 and PDE10A3 were produced only in cytosolic fractions of transfected PC12h cells. By contrast, recombinant PDE10A2 was present mainly in membrane fractions. This finding agreed well with the result of subcellular fractionation of PDE10A in rat striatum. Immunocytochemical analysis showed that PDE10A2 was localized in the Golgi apparatus of transfected PC12h cells. PDE10A2 was phosphorylated by cAMP-dependent protein kinase (PKA) at Thr 16 . Interestingly, recombinant protein of wild-type PDE10A2, but not PDE10A2 mutant with an Ala replacement at Thr 16 , was distributed to cytosolic fractions by co-transfection with a plasmid encoding the catalytic subunit of PKA. A PDE10A2 mutant with Glu substitution at Thr 16 , which can be a mimic of phosphorylation, was localized in the cytosolic fractions of transfected PC12h cells. These observations implied that phosphorylation of PDE10A2 at Thr 16 by PKA caused alteration of subcellular localization of PDE10A2 from the Golgi apparatus to cytosol. 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.Cyclic nucleotides, cAMP and cGMP, control physiological functions in neuronal networks. Dopamine, adenosine, and vasoactive intestinal peptide are neuronal transmitters and cause elevation of intracellular cAMP levels in striatal neurons (1-3). Cyclic AMP-dependent protein kinase (PKA), 1 which is activated by cAMP, phosphorylates certain receptors and intracellular proteins such as dopamine-and cAMP-related phosphoprotein of M r 32,000 (1) and glutamate receptor (4, 5) in striatal neurons. The cellular compartmentalization of cAMP signaling through association with several forms of protein kinase A-anchoring proteins (AKAPs), which interact with the regulatory subunit of PKA, has been discussed (6). Disorder of subcellular localization of PKA and AKAP prevents appropriate differentiation of PC12 cells stimulated by cAMP-producing agents (7). Thus, signal transduction by cyclic nucleotides is regulated by multiple components in neurons.Cyclic nucleotides are hydrolyzed by phosphodiesterases (PDEs), which consist of 11 families (8, 9). We have isolated cDNAs for a dual substrate PDE that hydrolyzes both cAMP and cGMP (PDE10A) from humans and rats (10), and another group has reported mouse PDE10A cDNA (11). K m values of PDE10A for cAMP and cGMP are 0.26 M and 7.2 M, respectively, and V max values for them are slightly different (10). We have previously reported that PDE10A transcrip...

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“…families have already been identified based on their substrate specificities, kinetic properties, allosteric regulators, inhibitor sensitivities, and amino acid sequences (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Within each family, several genes and splice variants have been recognized (2,11).…”

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confidence: 99%

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Wong

Whelan²,

Deloukas

et al. 2006

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

138

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Cyclic nucleotide phosphodiesterases (PDEs) constitute a family of enzymes that degrade cAMP and cGMP. Intracellular cyclic nucleotide levels increase in response to extracellular stimulation by hormones, neurotransmitters, or growth factors and are downregulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. cAMP is a second messenger implicated in learning, memory, and mood, and cGMP modulates nervous system processes that are controlled by the nitric oxide (NO)͞cGMP pathway. To investigate an association between genes encoding PDEs and susceptibility to major depressive disorder (MDD), we genotyped SNPs in 21 genes of this superfamily in 284 depressed Mexican Americans who participated in a prospective, double-blind, pharmacogenetic study of antidepressant response, and 331 matched controls. Polymorphisms in PDE9A and PDE11A were found to be associated with the diagnosis of MDD. Our data are also suggestive of the association between SNPs in other PDE genes and MDD. Remission on antidepressants was significantly associated with polymorphisms in PDE1A and PDE11A. Thus, we found significant associations with both the diagnosis of MDD and remission in response to antidepressants with SNPs in the PDE11A gene. We show here that PDE11A haplotype GAACC is significantly associated with MDD. We conclude that PDE11A has a role in the pathophysiology of MDD. This study identifies a potential CNS role for the PDE11 family. The hypothesis that drugs affecting PDE function, particularly cGMP-related PDEs, represent a treatment strategy for major depression should therefore be tested.gene association ͉ pharmacogenetics ͉ cGMP ͉ SNP ͉ Mexican American

show abstract

Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A

Cited by 353 publications

References 33 publications

Structural insight into substrate specificity of phosphodiesterase 10

Structural insight into substrate specificity of phosphodiesterase 10

Subcellular Localization of Cyclic Nucleotide Phosphodiesterase Type 10A Variants, and Alteration of the Localization by cAMP-dependent Protein Kinase-dependent Phosphorylation

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

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