Cloning and characterization of novel PDE4D isoforms PDE4D6 and PDE4D7

Wang, Daguang; Deng, Chunhua; Bugaj-Gaweda, Bozena; Kwan, May; Gunwaldsen, Caryn; Leonard, Christopher J.; Xin, Xiaonan; Hu, Yinghe; Unterbeck, A.; Vivo, Michael De

doi:10.1016/s0898-6568(03)00042-1

Cited by 49 publications

(53 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Comparing PDE4B5 to other PDE4 genes, we found that the novel 16 residues at the N terminus of PDE4B5 perfectly match the N terminus of the recently discovered super-short isoform of PDE4D, called PDE4D6 (Wang et al, 2003). Expanding on previous assessments (Wang et al, 2003), we found that the PDE4D6 transcript, like PDE4B5, is brainspecific.…”

Section: Pde4b5 a Novel Super-short Camp Phosphodiesterase-4 Variantsupporting

confidence: 62%

“…This isoform is highly conserved across species, is active, and responds to drug inhibition. We also show, for the first time, conservation between PDE4 subfamilies of an isoform-specific N-terminal region, with the PDE4B5 N-terminal isoform of PDE4B5 being identical to the N terminus of the super-short isoform encoded by the PDE4D gene, PDE4D6 (Wang et al, 2003).…”

mentioning

confidence: 66%

See 1 more Smart Citation

PDE4B5, a Novel, Super-Short, Brain-Specific cAMP Phosphodiesterase-4 Variant Whose Isoform-Specifying N-Terminal Region Is Identical to That of cAMP Phosphodiesterase-4D6 (PDE4D6)

Cheung

Kan²,

Garrett-Engele³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The cAMP-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential selective therapeutic inhibitors. The four PDE4 genes generate several distinct protein-coding isoforms through the use of alternative promoters and 5Ј-coding exons. Using mouse transcripts, we identified a novel, super-short isoform of human PDE4B encoding a novel 5Ј terminus, which we label PDE4B5. The protein-coding region of the novel 5Ј exon is conserved across vertebrates, chicken, zebrafish, and fugu. Reverse-transcription-polymerase chain reaction (PCR) and quantitative (PCR) measurements show that this isoform is brain-specific. The novel protein is 58 Ϯ 2 kDa; it has cAMP hydrolyzing enzymatic activity and is inhibited by PDE4-selective inhibitors rolipram and cilomilast (Ariflo). Confocal and subcellular fractionation analyses show that it is distributed predominantly and unevenly within the cytosol. The 16 novel N-terminal residues of PDE4B5 are identical to the 16 N-terminal residues of the super-short isoform of PDE4D (PDE4D6), which is also brain-specific. PDE4B5 is able to bind the scaffold protein DISC1, whose gene has been linked to schizophrenia. Microarray expression profiling of the PDE4 gene family shows that specific PDE4 genes are enriched in muscle and blood fractions; however, only by monitoring the individual isoforms is the brain specificity of the super-short PDE4D and PDE4B isoforms revealed. Understanding the distinct tissue specificity of PDE4 isoforms will be important for understanding phosphodiesterase biology and opportunities for therapeutic intervention.

show abstract

Section: Pde4b5 a Novel Super-short Camp Phosphodiesterase-4 Variantsupporting

confidence: 62%

mentioning

confidence: 66%

PDE4B5, a Novel, Super-Short, Brain-Specific cAMP Phosphodiesterase-4 Variant Whose Isoform-Specifying N-Terminal Region Is Identical to That of cAMP Phosphodiesterase-4D6 (PDE4D6)

Cheung

Kan²,

Garrett-Engele³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The gene encoding the supershort brain-specific isoform 6 of the phoshodiesterase 4D (PDE4D6) 59 including its presumed transcriptional control region is exclusively duplicated in patient 201. The duplication of PDE4D6 is inherited from the affected mother and located on chromsome 5q11.2, a region adjacent to the 5q13.1 locus of genome-wide significance in a high-resolution linkage study to ADHD (B2.5 Mb 5 0 of rs895381, family P1).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

et al. 2010

View full text Add to dashboard Cite

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental syndrome characterized by hyperactivity, inattention and increased impulsivity. To detect micro-deletions and micro-duplications that may have a role in the pathogenesis of ADHD, we carried out a genome-wide screen for copy number variations (CNVs) in a cohort of 99 children and adolescents with severe ADHD. Using high-resolution array comparative genomic hybridization (aCGH), a total of 17 potentially syndrome-associated CNVs were identified. The aberrations comprise 4 deletions and 13 duplications with approximate sizes ranging from 110 kb to 3 Mb. Two CNVs occurred de novo and nine were inherited from a parent with ADHD, whereas five are transmitted by an unaffected parent. Candidates include genes expressing acetylcholine-metabolizing butyrylcholinesterase (BCHE), contained in a de novo chromosome 3q26.1 deletion, and a brain-specific pleckstrin homology domaincontaining protein (PLEKHB1), with an established function in primary sensory neurons, in two siblings carrying a 11q13.4 duplication inherited from their affected mother. Other genes potentially influencing ADHD-related psychopathology and involved in aberrations inherited from affected parents are the genes for the mitochondrial NADH dehydrogenase 1 a subcomplex assembly factor 2 (NDUFAF2), the brain-specific phosphodiesterase 4D isoform 6 (PDE4D6) and the neuronal glucose transporter 3 (SLC2A3). The gene encoding neuropeptide Y (NPY) was included in a B3 Mb duplication on chromosome 7p15.2-15.3, and investigation of additional family members showed a nominally significant association of this 7p15 duplication with increased NPY plasma concentrations (empirical family-based association test, P = 0.023). Lower activation of the left ventral striatum and left posterior insula during anticipation of large rewards or losses elicited by functional magnetic resonance imaging links gene dose-dependent increases in NPY to reward and emotion processing in duplication carriers. These findings implicate CNVs of behaviour-related genes in the pathogenesis of ADHD and are consistent with the notion that both frequent and rare variants influence the development of this common multifactorial syndrome.

show abstract

“…Finally, PDE4 activity in the hippocampus is primarily attributed to PDE4D (Jin et al, 1999;Zhang et al, 2002), suggesting that changes in PDE4 activity induced by ERK-mediated phosphorylation involve this subtype to the greatest extent. Given that the shortform PDE4D variants are either somewhat activated (PDE4D1) or not affected (PDE4D2 and PDE4D6) by ERK activation , the long-form PDE4Ds, including PDE4D3, 4D4, 4D5, and 4D7 (Wang et al, 2003;O'Donnell and Zhang, 2004), could be the targets of ERK phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Phosphodiesterase 4 (PDE4) Enzyme Reverses Memory Deficits Produced by Infusion of the MEK Inhibitor U0126 into the CA1 Subregion of the Rat Hippocampus

Zhang

Zhao

Huang

et al. 2004

Neuropsychopharmacol

134

View full text Add to dashboard Cite

Cyclic AMP-specific phosphodiesterase 4 (PDE4), which is an integral component of NMDA receptor-mediated cAMP signaling, is involved in the mediation of memory processes. Given that NMDA receptors also mediate MEK/mitogen-activated protein kinase (MAPK, ERK) signaling, which is involved in synaptic plasticity, and that some PDE4 subtypes are phosphorylated and regulated by ERK, it was of interest to determine if PDE4 is involved in MEK/ERK signaling-mediated memory. It was found that rolipram, a PDE4-selective inhibitor, reversed the amnesic effect in the radial-arm maze test of the MEK inhibitor U0126 administered into the CA1 subregion of the rat hippocampus. Consistent with this, rolipram, either by peripheral administration or direct intra-CA1 infusion, enhanced the retrieval of long-term memory impaired by intra-CA1 infusion of U0126 using the step-through inhibitory avoidance test. The same dose of rolipram did not affect U0126-induced reduction of phospho-ERK1/2 levels in the CA1 subregion. However, in primary cultures of rat cerebral cortical neurons, pretreatment with U0126 increased PDE4 activity; this was correlated with the U0126-induced reduction of phospho-ERK1/2 levels. These results suggest that MEK/ERK signaling plays an inhibitory role in regulating PDE4 activity in the brain; this may be a novel mechanism by which MEK/ERK signaling mediates memory. PDE4 is likely to be an important link between the cAMP/PKA and MEK/ERK signaling pathways in the mediation of memory.

show abstract

Cloning and characterization of novel PDE4D isoforms PDE4D6 and PDE4D7

Cited by 49 publications

References 29 publications

PDE4B5, a Novel, Super-Short, Brain-Specific cAMP Phosphodiesterase-4 Variant Whose Isoform-Specifying N-Terminal Region Is Identical to That of cAMP Phosphodiesterase-4D6 (PDE4D6)

PDE4B5, a Novel, Super-Short, Brain-Specific cAMP Phosphodiesterase-4 Variant Whose Isoform-Specifying N-Terminal Region Is Identical to That of cAMP Phosphodiesterase-4D6 (PDE4D6)

Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree

Inhibition of the Phosphodiesterase 4 (PDE4) Enzyme Reverses Memory Deficits Produced by Infusion of the MEK Inhibitor U0126 into the CA1 Subregion of the Rat Hippocampus

Contact Info

Product

Resources

About