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First published on February 28, 2005; DOI: 10.1124/mol.104.009423

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Received for publication November 18, 2004.
Revised February 20, 2005.
Accepted for publication February 24, 2005.

Identification and characterisation of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cyclic AMP phosphodiesterase gene

Derek Wallace 1, LeeAnn Johnston 2, Elaine Huston 2, Douglas MacMaster 2, Thomas M Houslay 2, York-Fong Cheung 2, Lachlan Campbell 2, Jenni S Millen 2, Robin A Smith 3, Irene Gall 2, Richard G Knowles 3, Michael Sullivan 4, Miles D. Houslay 1*

1 University of Glasglow 2 Univ Glasgow 3 GSK 4 Astrazeneca

* Address correspondence to: E-mail: m.houslay{at}bio.gla.ac.uk

Abstract

PDE4A11 is a novel cAMP specific phosphodiesterase that is conserved in man, mouse, rat, pig and bat. Exon-14A11 encodes its unique, 81 amino acid N-terminal region. RT-PCR, done across the splice junction, plus identification of ESTs, identifies PDE4A11 as a long isoform, possessing UCR1 and UCR2 regulatory domains. Transcript analysis shows that PDE4A11 is widely expressed compared to PDE4A10 and PDE4A4B long isoforms. Truncation analysis identifies a putative promoter in a 250bp region located immediately upstream of the start site in Exon-14A11. Recombinant PDE4A11, expressed in COS7 cells, is a 126kDa protein localised predominantly around the nucleus and in membrane ruffles. PDE4A11 exhibits a Km for cAMP hydrolysis of 4µM with similar relative Vmax to PDE4A10 and PDE4A4B. PDE4A11 is dose-dependently inhibited by rolipram, Ro20-1724, 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 COS7 cells activates PDE4A11 concomitant with its phosphorylation at Ser119 by protein kinase A. PDE4A11 differs from PDE4A4 in sensitivity to cleavage by caspase-3, interaction with LYN SH3 domain, redistribution upon chronic rolipram challenge and sensitivity to certain PDE4 inhibitors. PDE4A11, PDE4A10 and PDE4A4 all can interact with {beta}arrestin. PDE4A11 is a novel, widely expressed long isoform that is activated by PKA phosphorylation and shows a distinct intracellular localisation, indicating that it may contribute to compartmentalised cAMP signalling in cells where it is expressed.


Key words: Phosphodiesterases, Protein Kinase A


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