Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling

Méhats, Céline; Andersen, Carsten; Filopanti, Marcello; Jin, S-L Catherine; Conti, Marco

doi:10.1016/s1043-2760(01)00523-9

Cited by 241 publications

(199 citation statements)

References 69 publications

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“…The human genome encodes 21 PDE genes and over 60 PDE isoforms categorized into 11 families (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). PDE molecules contain three regions: an N-terminal splicing region, a regulatory domain, and a catalytic domain near the C terminus.…”

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confidence: 99%

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Crystal Structures of Phosphodiesterases 4 and 5 in Complex with Inhibitor 3-Isobutyl-1-methylxanthine Suggest a Conformation Determinant of Inhibitor Selectivity

Huai

Liu

Francis

et al. 2004

Journal of Biological Chemistry

121

162

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Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes controlling cellular concentrations of the second messengers cAMP and cGMP. Crystal structures of the catalytic domains of cGMP-specific PDE5A1 and cAMP-specific PDE4D2 in complex with the nonselective inhibitor 3-isobutyl-1-methylxanthine have been determined at medium resolution. The catalytic domain of PDE5A1 has the same topological folding as that of PDE4D2, but three regions show different tertiary structures, including residues 79 -113, 208 -224 (H-loop), and 341-364 (M-loop) in PDE4D2 or 535-566, 661-676, and 787-812 in PDE5A1, respectively. Because H-and M-loops are involved in binding of the selective inhibitors, the different conformations of the loops, thus the distinct shapes of the active sites, will be a determinant of inhibitor selectivity in PDEs. IBMX binds to a subpocket that comprises key residues Ile-336, Phe-340, Gln-369, and Phe-372 of PDE4D2 or Val-782, Phe-786, Gln-817, and Phe-820 of PDE5A1. This subpocket may be a common site for binding nonselective inhibitors of PDEs.Cyclic nucleotide phosphodiesterases (PDEs) 1 hydrolyze cAMP and cGMP to 5Ј-AMP and 5Ј-GMP. The second messengers, cAMP and cGMP, mediate the response of cells to a wide variety of hormones and neurotransmitters and modulate many metabolic processes such as cardiac and smooth muscle contraction, glycogenolysis, platelet aggregation, secretion, lipolysis, ion channel conductance, apoptosis, and growth control (1-6).The human genome encodes 21 PDE genes and over 60 PDE isoforms categorized into 11 families (7-16). PDE molecules contain three regions: an N-terminal splicing region, a regulatory domain, and a catalytic domain near the C terminus. The 11 PDE families share a conserved catalytic domain of about 300 amino acids but rare homology in other regions across families. The function of the N-terminal splicing region of the PDE families is unknown. The regulatory domains of PDEs contain various structural motifs such as a calmodulin-binding domain in PDE1, upstream conserved region in PDE4, PAS (period clock protein, aryl hydrocarbon receptor nuclear translocator, and single-minded protein) domain in PDE8, GAF (cGMP-specific PDE, adenylyl cyclase, and Fh1A) domain in PDE2, -5, -6, -10, and -11. The regulatory domains have been shown to play roles in the regulation of the catalytic activity of PDEs or to participate in cross-talk with other signaling pathways (16 -18).PDEs share high degree (25-49%) of amino acid conservation in the catalytic domains, implying a similar three-dimensional structure of the catalytic domains. However, PDE families and isoforms within the respective family have varying substrate preferences for cAMP and cGMP. The PDE4, -7, and -8 families prefer to hydrolyze cAMP, whereas PDE5, -6, and -9 are cGMP-specific. PDE1, -2, -3, -10, and -11 show activities toward both substrates but have distinct K m values for cAMP and cGMP (16). In addition, many PDE families possess selective inhibitors that bind to the conserved active sit...

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confidence: 99%

“…The PDE4, -7, and -8 families prefer to hydrolyze cAMP, whereas PDE5, -6, and -9 are cGMP-specific. PDE1, -2, -3, -10, and -11 show activities toward both substrates but have distinct K m values for cAMP and cGMP (16). In addition, many PDE families possess selective inhibitors that bind to the conserved active site.…”

mentioning

confidence: 99%

Crystal Structures of Phosphodiesterases 4 and 5 in Complex with Inhibitor 3-Isobutyl-1-methylxanthine Suggest a Conformation Determinant of Inhibitor Selectivity

Huai

Liu

Francis

et al. 2004

Journal of Biological Chemistry

121

162

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“…Whereas PDE1 and PDE2 can hydrolyze both cAMP and cGMP, PDE3 preferentially hydrolyzes cAMP, and PDE4 is specific for cAMP. There is abundant biochemical evidence that PDE3 and PDE4 are activated by cAMP-dependent protein kinase (PKA) phosphorylation in several tissues, providing a putative negative feedback mechanism by which cAMP may regulate its own levels (15,16,17).A deeper understanding of the mechanisms involved in cAMP homeostasis requires appropriate methods for the direct and continuous measurement of the second messenger in intact cells. The approaches developed so far in cardiac myocytes are based on the use of fluorescent PKA as a biosensor of cAMP (18,14).…”

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confidence: 99%

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confidence: 99%

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Rochais

Vandecasteele

Lefebvre

et al. 2004

Journal of Biological Chemistry

131

141

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Intracardiac cAMP levels are modulated by hormones and neuromediators with specific effects on contractility and metabolism. To understand how the same second messenger conveys different information, mutants of the rat olfactory cyclic nucleotide-gated (CNG) channel ␣-subunit CNGA2, encoded into adenoviruses, were used to monitor cAMP in adult rat ventricular myocytes. CNGA2 was not found in native myocytes but was strongly expressed in infected cells. In whole cell patchclamp experiments, the forskolin analogue L-858051 (L-85) elicited a non-selective, Mg 2؉ -sensitive current observed only in infected cells, which was thus identified as the CNG current (I CNG ). The ␤-adrenergic agonist isoprenaline (ISO) also activated I CNG , although the maximal efficiency was Ϸ5 times lower than with L-85. However, ISO and L-85 exerted a similar maximal increase of the L-type Ca 2؉ current. The use of a CNGA2 mutant with a higher sensitivity for cAMP indicated that this difference is caused by the activation of a localized fraction of CNG channels by ISO. cAMP-dependent protein kinase (PKA) blockade with H89 or PKI, or phosphodiesterase (PDE) inhibition with IBMX, dramatically potentiated ISO-and L-85-stimulated I CNG . A similar potentiation of ␤-adrenergic stimulation occurred when PDE4 was blocked, whereas PDE3 inhibition had a smaller effect (by 2-fold). ISO and L-85 increased total PDE3 and PDE4 activities in cardiomyocytes, although this effect was insensitive to H89. However, in the presence of IBMX, H89 had no effect on ISO stimulation of I CNG . This study demonstrates that subsarcolemmal cAMP levels are dynamically regulated by a negative feedback involving PKA stimulation of subsarcolemmal cAMP-PDE.Recent evidence indicates that multimolecular signaling complexes between cell surface receptors and intracellular targets are essential for the speed and specificity of signal transduction events (1, 2, 3). However, how such modules maintain specificity when small diffusible molecules are generated during the signaling cascade is difficult to investigate. This question is particularly relevant for cAMP in the heart, where this cyclic nucleotide second messenger exerts diverse effects in response to a number of different neuromediators and hormones. For instance, the ␤-adrenergic agonist isoprenaline (ISO), 1 prostaglandin E 1 (PGE 1 ), and glucagon-like peptide 1 (GLP-1) elevate intracardiac cAMP levels with different effects on contractility; ISO augments the force of contraction, PGE 1 does not, and GLP-1 exerts a negative inotropic effect (4, 5). In order to explain these results, subcellular compartmentation of cAMP was proposed more than 20 years ago (6).Localized cAMP signals may be generated by the interplay between discrete production sites and restricted diffusion within the cytoplasm. In addition to specialized membrane structures that may circumvent cAMP spreading (6, 7), degradation of cAMP into 5Ј-AMP by cyclic nucleotide phosphodiesterases (PDEs) appears critical for the formation of dynamic microdomain...

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“…These isoforms show a peak of expression at birth. Given the role of PDE4 in hormonal pathways (Mehats et al, 2002), one may speculate that at birth, hormonal regulations of postnatal lung physiology begin to be tightly regulated by selective PDE4s. Notably, clearance of fetal lung fluid is initiated secondary to beta-adrenergic-stimulated Na þ transport near term or at birth (Finley et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Differential expression of cyclic nucleotide phosphodiesterases 4 in developing rat lung

López

Jarreau

Zana

et al. 2010

Developmental Dynamics

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During the perinatal period, lungs undergo changes to adapt to air breathing. The genes involved in these changes are developmentally regulated by various signaling pathways, including the cyclic nucleotide cAMP. As PDE4s are critical enzymes for regulation of cAMP levels, the objective of this study was to investigate PDE4's ontogeny in developing rat lung during the perinatal period. Pulmonary PDE4 activity, PDE4A-D, PDE4B, and PDE4D variant expression levels, PDE4B and PDE4D protein levels, and PDE4D localization in distal lung were determined. PDE4 activity increased towards term, dropped at birth, and increased thereafter to reach a plateau at the end of the second week of life. PDE4B2 and PDE4D long forms demonstrated a pattern of expression that increased markedly at birth. After birth, PDE4D was expressed in alveolar epithelial and mesenchymal cells. The study, therefore, evidenced striking variations in expression patterns among the PDE4 family that differed from changes in global PDE4 activity. Developmental Dynamics 239:2470-2478,

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Cyclic nucleotide phosphodiesterases and their role in endocrine cell signaling

Cited by 241 publications

References 69 publications

Crystal Structures of Phosphodiesterases 4 and 5 in Complex with Inhibitor 3-Isobutyl-1-methylxanthine Suggest a Conformation Determinant of Inhibitor Selectivity

Crystal Structures of Phosphodiesterases 4 and 5 in Complex with Inhibitor 3-Isobutyl-1-methylxanthine Suggest a Conformation Determinant of Inhibitor Selectivity

Negative Feedback Exerted by cAMP-dependent Protein Kinase and cAMP Phosphodiesterase on Subsarcolemmal cAMP Signals in Intact Cardiac Myocytes

Differential expression of cyclic nucleotide phosphodiesterases 4 in developing rat lung

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