Structure, Localization, and Regulation of cGMP-inhibited Phosphodiesterase (PDE3)

Abstract

cAMP and cGMP mediate biological responses initiated by diverse extracellular signals. By catalyzing hydrolysis of the 3′-5′-phosphodiester bond of cyclic nucleotides, cyclic nucleotide phosphodiesterases (PDEs) 1The abbreviations used are: PDEphosphodiesteraseHSLhormone-sensitive lipasePDE3IKPDE3B insulin-sensitive kinasePI3-Kphosphatidylinositol 3-kinaseIRS-1insulin receptor substrate-1. regulate intracellular concentrations and effects of these second messengers. PDEs include a large group of structurally related enzymes (reviewed in 1Manganiello V.C. Murata T. Taira M. Belfrage P. Degerman E. Arch. Biochem. Biophys. 1995; 322: 1-13Crossref PubMed Scopus (223) Google Scholar, 2Conti M. Nemos G. Sette C. Vicini E. Endocr. Rev. 1995; 16: 370-389Crossref PubMed Scopus (317) Google Scholar, 3Beavo J. Physiol. Rev. 1995; 75: 725-748Crossref PubMed Scopus (1647) Google Scholar). These enzymes belong to at least seven related gene families (PDEs 1-7) (Fig. 1), which differ in their primary structures, affinities for cAMP and cGMP, responses to specific effectors, sensitivities to specific inhibitors, and mechanisms of regulation (1Manganiello V.C. Murata T. Taira M. Belfrage P. Degerman E. Arch. Biochem. Biophys. 1995; 322: 1-13Crossref PubMed Scopus (223) Google Scholar, 2Conti M. Nemos G. Sette C. Vicini E. Endocr. Rev. 1995; 16: 370-389Crossref PubMed Scopus (317) Google Scholar, 3Beavo J. Physiol. Rev. 1995; 75: 725-748Crossref PubMed Scopus (1647) Google Scholar). Most families are comprised of more than one gene; 14 different PDE genes have been identified. Within different families, tissue-specific mRNAs are generated from the same gene by the use of different transcription initiation sites or by alternative mRNA splicing. Although some aspects of different PDE families will be discussed, this review emphasizes the PDE3 family, including structure-function information and regulation of the adipocyte PDE3, which plays a key role in the antilipolytic action of insulin. phosphodiesterase hormone-sensitive lipase PDE3B insulin-sensitive kinase phosphatidylinositol 3-kinase insulin receptor substrate-1. Mammalian PDEs share a common structural organization, with a conserved catalytic core (∼270 amino acids) usually located in the C-terminal half (Fig. 1) (4Charbonneau H. Beier N. Walsh K.A. Beavo J.A. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 9308-9312Crossref PubMed Scopus (112) Google Scholar). This region is much more similar within an individual PDE family (>80% amino acid identity) than between different PDE families (∼25-40% identity) (1Manganiello V.C. Murata T. Taira M. Belfrage P. Degerman E. Arch. Biochem. Biophys. 1995; 322: 1-13Crossref PubMed Scopus (223) Google Scholar, 2Conti M. Nemos G. Sette C. Vicini E. Endocr. Rev. 1995; 16: 370-389Crossref PubMed Scopus (317) Google Scholar, 3Beavo J. Physiol. Rev. 1995; 75: 725-748Crossref PubMed Scopus (1647) Google Scholar, 4Charbonneau H. Beier N. Walsh K.A. Beavo J.A. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 9308-9312Crossref PubMed Scopus (112) Google Scholar). The catalytic core is thought to contain common structural elements important for hydrolysis of the cyclic nucleotide phosphodiester bond, as well as family-specific determinants responsible for differences in substrate affinities and inhibitor sensitivities among the different gene families. It contains a PDE-specific sequence motif, HD(X)2H(X4)N, and two consensus Zn2+-binding domains, the second of which overlaps the PDE motif (3Beavo J. Physiol. Rev. 1995; 75: 725-748Crossref PubMed Scopus (1647) Google Scholar, 5Francis S.H. Colbran J.L. McAllister-Lucas L.M. Corbin J.D. J. Biol. Chem. 1994; 269: 22477-22480Abstract Full Text PDF PubMed Google Scholar). PDE5 contains tightly bound Zn2+, which supports catalytic activity (5Francis S.H. Colbran J.L. McAllister-Lucas L.M. Corbin J.D. J. Biol. Chem. 1994; 269: 22477-22480Abstract Full Text PDF PubMed Google Scholar). The precise role of Zn2+ or other divalent cations in catalytic function of other PDEs has not been defined. Mutagenesis of the first histidine of the PDE sequence motif abolished activity of a recombinant PDE4 expressed in Escherichia coli (6Jin S.-L. Swinnen J.V. Conti M. J. Biol. Chem. 1992; 267: 18929-18939Abstract Full Text PDF PubMed Google Scholar). Histidine- and sulfhydryl-modifying reagents inhibited PDE3 activity (7Omburo G.A. Brickus T. Ghazaleh F. Colman R.W. Arch. Biochem. Biophys. 1995; 323: 1-5Crossref PubMed Scopus (25) Google Scholar). The widely divergent N-terminal portions of PDEs (Fig. 1) contain determinants that confer regulatory properties specific to the different gene families, e.g. calmodulin-binding domains (PDE1); two non-catalytic cyclic nucleotide-binding domains (PDEs 2, 5, and 6); N-terminal membrane-targeting (PDE4) or hydrophobic membrane-association (PDE3) domains; and calmodulin (PDE1)-, cyclic AMP (PDEs 1, 3, and 4)-, and cGMP (PDE5)-dependent protein kinase phosphorylation sites, etc. (Fig