Article
- The EMBO Journal (2006) 25, 2051 - 2061
- doi:10.1038/sj.emboj.7601113
Published online: 27 April 2006
Subject Categories:
An anchored PKA and PDE4 complex regulates subplasmalemmal cAMP dynamics
Debbie Willoughby1, Wei Wong2, Jerome Schaack3, John D Scott2 and Dermot M F Cooper1
- Department of Pharmacology, University of Cambridge, Cambridge, UK
- Howard Hughes Medical Institute/Vollum Institute, Oregon Health & Science University, Portland, OR, USA
- Department of Microbiology, Program in Molecular Biology, and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, CO, USA
Correspondence to:
Dermot M F Cooper, Department of Pharmacology, Tennis Court Road, University of Cambridge, Cambridge CB2 1QJ, UK. Tel.: +44 1223 334063; Fax: +44 1223 334040; E-mail: dmfc2@cam.ac.uk
Received 23 November 2005; Accepted 3 April 2006
Abstract
The spatiotemporal regulation of cAMP can generate microdomains just beneath the plasma membrane where cAMP increases are larger and more dynamic than those seen globally. Real-time measurements of cAMP using mutant cyclic nucleotide-gated ion channel biosensors, pharmacological tools and RNA interference (RNAi) were employed to demonstrate a subplasmalemmal cAMP signaling module in living cells. Transient cAMP increases were observed upon stimulation of HEK293 cells with prostaglandin E1. However, pretreatment with selective inhibitors of type 4 phosphodiesterases (PDE4), protein kinase A (PKA) or PKA/A-kinase anchoring protein (AKAP) interaction blocked an immediate return of subplasmalemmal cAMP to basal levels. Knockdown of specific membrane-associated AKAPs using RNAi identified gravin (AKAP250) as the central organizer of the PDE4 complex. Co-immunoprecipitation confirmed that gravin maintains a signaling complex that includes PKA and PDE4D. We propose that gravin-associated PDE4D isoforms provide a means to rapidly terminate subplasmalemmal cAMP signals with concomitant effects on localized ion channels or enzyme activities.
Keywords:
- AKAP,
- cAMP,
- microdomain,
- PDE4,
- PKA
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Kinase- and phosphatase-anchoring proteins: harnessing the dynamic duo
Nature Cell Biology Review (01 Aug 2002)
NEWS AND VIEWS
Nature Cell Biology News and Views (01 Sep 2000)
A-kinase anchoring proteins: different partners, different dance
Nature Cell Biology News and Views (01 Nov 2005)
RESEARCH
Protein kinase A regulates AKAP250 (gravin) scaffold binding to the β 2 -adrenergic receptor
The EMBO Journal Article (15 Dec 2003)
Protein kinase A regulates AKAP250 (gravin) scaffold binding to the β 2 -adrenergic receptor
The EMBO Journal Article (15 Dec 2003)
