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First published online 29 August 2006
doi: 10.1242/jcs.03106

Journal of Cell Science 119, 3799-3810 (2006)
Published by The Company of Biologists 2006
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Research Article

Helix-1 of the cAMP-specific phosphodiesterase PDE4A1 regulates its phospholipase-D-dependent redistribution in response to release of Ca2+

Elaine Huston1, Irene Gall1, Thomas M. Houslay2 and Miles D. Houslay1,*

1 Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences
2 Bioinformatics Research Centre, Davidson Building, University of Glasgow, Glasgow, G12 8QQ, Scotland, UK

* Author for correspondence (e-mail: m.houslay{at}bio.gla.ac.uk)

Accepted 19 June 2006

The unique N-terminal regions of PDE4 cAMP-specific phosphodiesterases confer interaction with distinct signalling and scaffolding proteins. The PDE4A1 isoform is unique in being entirely membrane associated. Its N-terminal region is formed from two helices separated by a mobile hinge, where helix-2 contains a TAPAS1 domain that inserts into the lipid bilayer in a Ca2+-triggered fashion. Here we show that helix-1 is important for intracellular targeting of PDE4A1 in living cells, facilitating membrane association, targeting to the trans-Golgi stack and conferring Ca2+-stimulated intracellular redistribution in a manner that is dependent on the phospholipase-D-mediated generation of phosphatidic acid. The LxDFF motif within helix-1 is pivotal to this, where Leu4-Phe6-Phe7 forms a compact hydrophobic pocket on one side of helix-1 whereas Asp5, located on the opposite face of helix-1, provides the Ca2+-regulation site. Mutation of Asp5 to Ala or the release of Ca2+ from intracellular stores de-restricts trans-Golgi localisation of PDE4A1 allowing it to redistribute in cells in a phosphatidic-acid-dependent manner. This study provides the first evidence for Ca2+-triggered relocalisation of a cAMP phosphodiesterase and indicates a potential means for allowing cross-talk between the cAMP, phospholipase D and Ca2+-signalling pathways.

Key words: PDE4A, Cyclic AMP, Trafficking, Ca2+, Phosphatidic acid, Golgi






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