Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP-hydrolytic activity in subcellular fractions of human myocardium

doi:10.1074/jbc.M506760200

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Isoforms of cyclic nucleotide phosphodiesterase PDE3 and their contribution to cAMP-hydrolytic activity in subcellular fractions of human myocardium

Ryan Hambleton, Judith Krall, Eliso Tikishvili, Matthew Honeggar, Faiyaz Ahmad, Vincent C. Manganiello, and Matthew A. Movsesian

Cardiology Section, VA Salt Lake City Health Care System, Salt Lake City, UT 84148

Corresponding Author: matthew.movsesian{at}hsc.utah.edu

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 using recombinant proteins, determined their contribution to cAMP hydrolysis in cytosolic and microsomal fractions of human myocardium at 0.1 µM and 1.0 µM cAMP in the absence and presence of Ca2+/calmodulin, and examined the effects of cGMP on cAMP hydrolysis in these fractions. PDE3A-136, PDE3A-118 and PDE3A-94 have similar Km’s and kcat’s 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.

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