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J. Biol. Chem., Vol. 280, Issue 3, 1716-1719, January 21, 2005
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From the
Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany, the ¶Institute of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Wurzburg, Germany, and the ||Rudolf-Virchow-Center for Experimental Biomedicine, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany
Cyclic nucleotide phosphodiesterases (PDEs) are the enzymes that catalyze the hydrolysis of cAMP and cGMP, thereby restricting the activity of these second messengers in cells. A unique ability to shape gradients of cyclic nucleotides and compartmentalize their signaling implies a high potency and a rapid action of PDEs. However, it has not been demonstrated how fast PDEs can hydrolyze cAMP in a living system. Here we perform a real-time monitoring of PDE2 activity in aldosterone-producing adrenal cells using a recently developed genetically encoded, fluorescent cAMP sensor, which reveals enormously rapid kinetics of cAMP degradation. Activation of PDE2 results in a rapid decrease of intracellular cAMP from high micromolar to the sub-micromolar range within a few seconds. Moreover, the kinetics of atrial natriuretic peptide-stimulated PDE2 activity (measured as decline of cAMP) are much faster than the speed of ACTH and isoprenaline-induced cAMP-synthesis (measured as cAMP accumulation) in the cells, revealing high catalytic activity and fast action of PDEs in regulating cAMP signaling in a physiological system.
Received for publication, October 25, 2004 , and in revised form, November 22, 2004.
* This work was supported by the Deutsche Forschungsgemeinschaft (Grants WA366 and SFB487 and Leibniz Award to M. J. L.), the Fonds der Chemischen Industrie, and the Bayerische Forschungsstiftung: For Nano. 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.
These authors contributed equally to this work.
** To whom correspondence should be addressed. Tel.: 49-931-201-48400; Fax: 49-931-201-48411; E-mail: lohse{at}toxi.uni-wuerzburg.de.
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