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Molecular Pharmacology

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Research ArticleArticle

Identification and Characterization of PDE4A11, a Novel, Widely Expressed Long Isoform Encoded by the Human PDE4A cAMP Phosphodiesterase Gene

Derek A. Wallace, Lee Ann Johnston, Elaine Huston, Douglas MacMaster, Thomas M. Houslay, York-Fong Cheung, Lachlan Campbell, Jenni E. Millen, Robin A. Smith, Irene Gall, Richard G. Knowles, Michael Sullivan and Miles D. Houslay
Molecular Pharmacology June 2005, 67 (6) 1920-1934; DOI: https://doi.org/10.1124/mol.104.009423
Derek A. Wallace
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Lee Ann Johnston
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Elaine Huston
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Douglas MacMaster
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Thomas M. Houslay
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York-Fong Cheung
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Lachlan Campbell
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Jenni E. Millen
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Robin A. Smith
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Irene Gall
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Richard G. Knowles
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Michael Sullivan
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Miles D. Houslay
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Abstract

PDE4A11 is a novel cAMP-specific phosphodiesterase that is conserved in humans, mouse, rat, pig, and bat. Exon-14A11 encodes its unique, 81 amino acid N-terminal region. Reverse-transcriptase polymerase chain reaction performed across the splice junction, plus identification of expressed sequence tags, identifies PDE4A11 as a long isoform possessing UCR1 and UCR2 regulatory domains. Transcript analysis shows that PDE4A11 is widely expressed compared with PDE4A10 and PDE4A4B long isoforms. Truncation analysis identifies a putative promoter in a 250-base pair region located immediately upstream of the start site in Exon-14A11. Recombinant PDE4A11, expressed in COS-7 cells, is a 126-kDa protein localized predominantly around the nucleus and in membrane ruffles. PDE4A11 exhibits a Km for cAMP hydrolysis of 4 μM, with relative Vmax similar to that of PDE4A10 and PDE4A4B. PDE4A11 is dose-dependently inhibited by rolipram, 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone (Ro 20-1724), cilomilast, roflumilast, and denbufylline, with IC50 values of 0.7, 0.9, 0.03, 0.004, and 0.3 μM, respectively. Soluble and particulate PDE4A11 exhibit distinct rates of thermal inactivation (55°C; T(0.5) = 2.5 and 4.4 min, respectively). Elevating cAMP levels in COS-7 cells activates PDE4A11 concomitant with its phosphorylation at Ser119 by protein kinase A (PKA). PDE4A11 differs from PDE4A4 in sensitivity to cleavage by caspase-3, interaction with LYN SH3 domain, redistribution upon long-term rolipram challenge, and sensitivity to certain PDE4 inhibitors. PDE4A11, PDE4A10, and PDE4A4 all can interact with βarrestin. PDE4A11 is a novel, widely expressed long isoform that is activated by PKA phosphorylation and shows a distinct intracellular localization, indicating that it may contribute to compartmentalized cAMP signaling in cells in which it is expressed.

  • Received November 17, 2004.
  • Accepted February 24, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (6)
Molecular Pharmacology
Vol. 67, Issue 6
1 Jun 2005
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Research ArticleArticle

Identification and Characterization of PDE4A11, a Novel, Widely Expressed Long Isoform Encoded by the Human PDE4A cAMP Phosphodiesterase Gene

Derek A. Wallace, Lee Ann Johnston, Elaine Huston, Douglas MacMaster, Thomas M. Houslay, York-Fong Cheung, Lachlan Campbell, Jenni E. Millen, Robin A. Smith, Irene Gall, Richard G. Knowles, Michael Sullivan and Miles D. Houslay
Molecular Pharmacology June 1, 2005, 67 (6) 1920-1934; DOI: https://doi.org/10.1124/mol.104.009423

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Research ArticleArticle

Identification and Characterization of PDE4A11, a Novel, Widely Expressed Long Isoform Encoded by the Human PDE4A cAMP Phosphodiesterase Gene

Derek A. Wallace, Lee Ann Johnston, Elaine Huston, Douglas MacMaster, Thomas M. Houslay, York-Fong Cheung, Lachlan Campbell, Jenni E. Millen, Robin A. Smith, Irene Gall, Richard G. Knowles, Michael Sullivan and Miles D. Houslay
Molecular Pharmacology June 1, 2005, 67 (6) 1920-1934; DOI: https://doi.org/10.1124/mol.104.009423
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