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

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical & Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom (D.A.W., L.A.J., E.H., D.M., T.M.H., Y.-F.C., L.C., J.E.M., I.G., M.D.H.); GlaxoSmithKline, Respiratory Pharmacology, Stevenage, Herts, United Kingdom (R.A.S., R.G.K.); and Astra Charnwood, Loughborough, United Kingdom (M.S.)

PDE4A11 is a novel cAMP-specific phosphodiesterase that is conserved in humans, mouse, rat, pig, and bat. Exon-1^4A11 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-1^4A11. Recombinant PDE4A11, expressed in COS-7 cells, is a 126-kDa protein localized predominantly around the nucleus and in membrane ruffles. PDE4A11 exhibits a K_m for cAMP hydrolysis of 4 µM, with relative V_max 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 arrestin. 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 for publication November 17, 2004.

Accepted for publication February 24, 2005.

Address correspondence to: Dr. Miles D Houslay, Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology., Institute of Biomedical and Life Sciences, Wolfson Building, University Avenue, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. E-mail: m.houslay{at}bio.gla.ac.uk

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