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J. Biol. Chem., Vol. 282, Issue 47, 34235-34249, November 23, 2007

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Dynamic Regulation, Desensitization, and Cross-talk in Discrete Subcellular Microdomains during ₂-Adrenoceptor and Prostanoid Receptor cAMP Signaling^*

Debbie Willoughby, George S. Baillie, Martin J. Lynch, Antonio Ciruela, Miles D. Houslay, and Dermot M. F. Cooper, A Royal Society Wolfson Research Fellow¹

From the Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD and the Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, Wolfson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom

Dynamic and localized actions of cAMP are central to the generation of discrete cellular events in response to a range of G_s-coupled receptor agonists. In the present study we have employed a cyclic nucleotide-gated channel sensor to report acute changes in cAMP in the restricted cellular microdomains adjacent to two different G_s-coupled receptor pathways, ₂-adrenoceptors and prostanoid receptors that are expressed endogenously in HEK293 cells. We probed by either selective small interference RNA-mediated knockdown or dominant negative overexpression the contribution of key signaling components in the rapid attenuation of the local cAMP signaling and subsequent desensitization of each of these G-protein-coupled receptor signaling pathways immediately following receptor activation. Direct measurements of cAMP changes just beneath the plasma membrane of single HEK293 cells reveal novel insights into key regulatory roles provided by protein kinase A-RII, -arrestin2, cAMP phosphodiesterase-4D3, and cAMP phosphodiesterase-4D5. We provide new evidence for distinct modes of cAMP down-regulation in these two G_s-linked pathways and show that these distinct G-protein-coupled receptor signaling systems are subject to unidirectional, heterologous desensitization that allows for limited cross-talk between distinct, dynamically regulated pools of cAMP.

Received for publication, August 14, 2007 , and in revised form, September 5, 2007.

^* This work was supported in part by Wellcome Trust Grant RG31760 (to D. M. F. C.), National Institutes of Health Grant NS28389 (to D. M. F. C.), Medical Research Council (UK) Grant G8604010 (to M. D. H.), and European Union Grant QLK3-CT-2002-02149 (to M. D. H. and D. M. F. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 44-1223-334-063; Fax: 44-1223-334-100; E-mail: dmfc2{at}cam.ac.uk.

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