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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.

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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