JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 22, 2007; DOI: 10.1124/jpet.107.122218

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.107.122218v1
322/2/600    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cheung, Y.-F.
Right arrow Articles by Castle, J. C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cheung, Y.-F.
Right arrow Articles by Castle, J. C


Received for publication March 5, 2007.
Revised May 18, 2007.
Accepted for publication May 21, 2007.

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)

York-Fong Cheung 1, Zhengyan Kan 2, Philip Garrett-Engele 2, Irene Gall 1, Hannah Murdoch 1, George S Baillie 1, Luiz Miguel Camargo 3, Jason M Johnson 2, Miles D Houslay 1, John C Castle 2*

1 University of Glasgow 2 Rosetta Inpharmatics LLC 3 Merck Research Laboratories

* Address correspondence to: E-mail: john_castle{at}merck.com

Abstract

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 5' coding exons. Using mouse transcripts, we identified a novel, super-short isoform of human PDE4B encoding a novel 5' terminus, which we label PDE4B5. The protein coding region of the novel 5' exon is conserved across vertebrates, chicken, zebrafish, and fugu. RT-PCR and qPCR measurements show this isoform is brain-specific. The novel protein is 58 ± 2 kDa; has cAMP hydrolyzing enzymatic activity and is inhibited by PDE4 selective inhibitors rolipram and ariflo (cilomilast). Confocal and sub-cellular 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.


Key words: PDE4B, alternative promoters, alternative splicing, cAMP phosphodiesterase, gene expression, schizophrenia


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
T. B. Halene and S. J. Siegel
Antipsychotic-Like Properties of Phosphodiesterase 4 Inhibitors: Evaluation of 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724) with Auditory Event-Related Potentials and Prepulse Inhibition of Startle
J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 230 - 239.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
U. Tawar, K. Kotlo, S. Jain, S. Shukla, S. Setty, and R. S. Danziger
Renal Phosphodiesterase 4B Is Activated in the Dahl Salt-Sensitive Rat
Hypertension, March 1, 2008; 51(3): 762 - 766.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
J. K. Millar, S. Mackie, S. J. Clapcote, H. Murdoch, B. S. Pickard, S. Christie, W. J. Muir, D. H. Blackwood, J. C. Roder, M. D. Houslay, et al.
Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness
J. Physiol., October 15, 2007; 584(2): 401 - 405.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.