Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase

Koesling

Journal of Biological Chemistry

2015

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: Camp-dependent Phosphorylation Of Pde10a Occurs In Vivo and Ismentioning

confidence: 95%

“…PDE10 was initially discovered in brain and is capable of hydrolyzing both second messengers, cAMP and cGMP, but has higher affinity for cAMP (2)(3)(4). PDE10 contains a tandem of regulatory GAF domains.…”

mentioning

confidence: 99%

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

Koesling

Journal of Biological Chemistry

2015

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

“…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

103

139

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...

Journal of Biological Chemistry

“…We therefore performed in situ hybridization on the Pde10A gene using sections of rat brains in which LTP was induced and followed for 1 h. Because the Pde10A gene is subjected to alternative splicing (41,42,47,48), we performed in situ hybridization on several of these variants (oligonucleotide probes YC-YG, location indicated in Fig. 2).…”

Section: Fig 1 Differential Display Of Gene Expression In Ltpmentioning

confidence: 99%

Differential Amplification of Intron-containing Transcripts Reveals Long Term Potentiation-associated Up-regulation of Specific Pde10A Phosphodiesterase Splice Variants

O’Connor

Génin

Davis

et al. 2004

We employed differential display of expressed mRNAs (Liang, P., and Pardee, A. B. (1992) Science 257, 967-971) to identify genes up-regulated after long term potentiation (LTP) induction in the hippocampus of awake adult rats. In situ hybridization confirmed the differential expression of five independently amplified clones representing two distinct transcripts, cl13/19/90 and cl95/96. Neither cl13/19/90 nor cl95/96 showed significant sequence homology to known transcripts (mRNA or expressed sequence tag) or to the mouse or human genome. However, comparison with the rat genome revealed that they are localized to a predicted intron of the phosphodiesterase Pde10A gene. cl13/19/90 and cl95/96 are likely to be part of the Pde10A primary transcript as, using reverse transcriptase-PCR, we could specifically amplify distinct introns of the Pde10A primary transcript, and in situ hybridization demonstrated that a subset of Pde10A splice variants are also up-regulated after LTP induction. These results indicate that amplification of a primary transcript can faithfully report gene activity and that differential display can be used to identify differential expression of RNA species other than mRNA. In transiently transfected Cos7 cells, Pde10A3 reduces the atrial natriuretic peptide-induced elevation in cGMP levels without affecting basal cGMP levels. This cellular function of LTP-associated Pde10A transcripts argues for a role of the cGMP/cGMP-dependent kinase pathway in long term synaptic plasticity.Memory, the recollection of acquired information, is encoded in the brain as enduring changes in distributed neural networks. Synapses that support activity-dependent changes in synaptic efficacy are therefore a likely location of information storage in the brain. Long term potentiation (LTP) 1 is an activitydependent long lasting increase in synaptic efficacy in the hippocampus and other cortical structures and is the main cellular model for learning and memory (2). There is strong evidence indicating that LTP constitutes a neural substrate for some forms of learning and memory (3): (i) both LTP and learning depend on the activation of similar signal transduction cascades (4); (ii) animal models in which the induction of LTP is impaired are generally also impaired in hippocampaldependent learning and memory (see, e.g., Refs. 5-8, but see Ref. 9); (iii) mice that show enhanced LTP also show enhanced learning and memory (10, 11); and (iv) behavioral paradigms can induce an increase in the synaptic strength in the amygdala (12).Another point of congruence is the requirement for de novo RNA and protein synthesis both for the formation of long term memory (13,14) and the late stage of LTP, L-LTP (15-17). The observation that L-LTP requires de novo RNA and protein synthesis has led to a search for genes that are modulated by LTP. To date, several transcripts have been identified and include both transcription factors (e.g. Zif268) (18 -20), as well as proteins with a cellular and/or synaptic function (20 -26). In addition to de ...