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Vol. 59, Issue 5, 996-1011, May 2001

Molecular Cloning, Genomic Positioning, Promoter Identification, and Characterization of the Novel Cyclic AMP-Specific Phosphodiesterase PDE4A10

Graham Rena,1 Fiona Begg,2 Annette Ross,3 Carolynn MacKenzie, Ian McPhee,4 Lachlan Campbell, Elaine Huston, Michael Sullivan,5 and Miles D. Houslay

Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom

We describe the cloning and expression of HSPDE4A10, a novel long form splice variant of the human cAMP phosphodiesterase PDE4A gene. The 825 amino acid HSPDE4A10 contains a unique N terminus of 46 amino acids encoded by a unique 5' exon. Exon-14A10 lies ~11 kilobase pairs (kb) downstream of exon-14A4 and ~13.5 kb upstream of the PDE4A common exon 2. We identify a rat PDE4A10 ortholog and reveal a murine ortholog by nucleotide sequence database searching. PDE4A10 transcripts were detected in various human cell lines and tissues. The 5' sequence flanking exon-14A10 exhibited promoter activity with the minimal functional promoter region being highly conserved in the corresponding mouse genomic sequence. Transient expression of the engineered human PDE4A10 open reading frame in COS7 cells allowed detection of a 121-kDa protein in both soluble and particulate fractions. PDE4A10 was localized primarily to the perinuclear region of COS7 cells. Soluble and particulate forms exhibited similar Km values for cAMP hydrolysis (3-4 µM) and IC50 values for inhibition by rolipram (50 nM) but the Vmax value of the soluble form was ~3-fold greater than that of the particulate form. At 55°C, soluble HSPDE4A10 was more thermostable (T0.5 = 11 min) than the particulate enzyme (T0.5 = 5 min). HSPDE4A10 and HSPDE4A4B are shown here to be similar in size and exhibit similar maximal activities but differ with respect to sensitivity to inhibition by rolipram, thermostability, interaction with the SRC homology 3 domain of LYN, an SRC family tyrosyl kinase, and subcellular localization. We suggest that the unique N-terminal regions of PDE4A isoforms confer distinct properties upon them.

1 Current address: MRC Protein Phosphorylation Unit, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, Scotland.

2 Current address: Grant Management, 20-23 Woodside Place, Glasgow G3 7QF, Scotland, UK.

3 Current address: Department of Botany, University of Cambridge, Cambridge, CB12 1QW, England, UK.

4 Current address: Scottish Biomedical, Block H, Ground Floor, Telford Pavilion, Todd Campus West of Scotland Science Park, Glasgow G20 0XA, Scotland, UK.

5 Current address: AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, England, UK.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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