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J. Biol. Chem., Vol. 280, Issue 47, 39168-39174, November 25, 2005

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Isoforms of Cyclic Nucleotide Phosphodiesterase PDE3 and Their Contribution to cAMP Hydrolytic Activity in Subcellular Fractions of Human Myocardium^*

Ryan Hambleton1, Judith Krall1, Eliso Tikishvili, Matthew Honeggar, Faiyaz Ahmad¶, Vincent C. Manganiello¶, and Matthew A. Movsesian2

From the Cardiology Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah 84148, the Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah 84132, and the ^¶Pulmonary-Critical Care Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892

Three isoforms of PDE3 (cGMP-inhibited) cyclic nucleotide phosphodiesterase regulate cAMP content in different intracellular compartments of cardiac myocytes in response to different signals. We characterized the catalytic activity and inhibitor sensitivity of these isoforms by using recombinant proteins. We determined their contribution to cAMP hydrolysis in cytosolic and microsomal fractions of human myocardium at 0.1 and 1.0 µM cAMP in the absence and presence of Ca²⁺/calmodulin. We examined the effects of cGMP on cAMP hydrolysis in these fractions. PDE3A-136, PDE3A-118, and PDE3A-94 have similar K_m and k_cat values for cAMP and are equal in their sensitivities to inhibition by cGMP and cilostazol. In microsomes, PDE3A-136, PDE3A-118, and PDE3A-94 comprise the majority of cAMP hydrolytic activity under all conditions. In cytosolic fractions, PDE3A-118 and PDE3A-94 comprise >50% of the cAMP hydrolytic activity at 0.1 µM cAMP, in the absence of Ca²⁺/calmodulin. At 1.0 µM cAMP, in the presence of Ca²⁺/calmodulin, activation of Ca²⁺/calmodulin-activated (PDE1) and other non-PDE3 phosphodiesterases reduces their contribution to <20% of cAMP hydrolytic activity. cGMP inhibits cAMP hydrolysis in microsomal fractions by inhibiting PDE3 and in cytosolic fractions by inhibiting both PDE3 and PDE1. These findings indicate that the contribution of PDE3 isoforms to the regulation of cAMP hydrolysis in intracellular compartments of human myocardium and the effects of PDE3 inhibition on cAMP hydrolysis in these compartments are highly dependent on intracellular [Ca²⁺] and [cAMP], which are lower in failing hearts than in normal hearts. cGMP may amplify cAMP-mediated signaling in intracellular compartments of human myocardium by PDE3-dependent and PDE3-independent mechanisms.

Received for publication, June 21, 2005 , and in revised form, August 30, 2005.

^* This work was supported by medical research funds from the Department of Veterans Affairs, the American Heart Association, and the University of Utah Research Foundation. 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Cardiology Section, Veterans Affairs Salt Lake City Health Care System, 500 Foothill Blvd., Salt Lake City, UT 84148. Tel.: 801-582-1565 (ext. 4156); Fax: 801-584-2532; E-mail: matthew.movsesian{at}hsc.utah.edu.

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