Effects of Phosphodiesterase Inhibitors on Cyclic Amp Levels and on Lipolysis*

Beavo, Joseph A.; Rogers, N. L.; Crofford, Oscar B.; Baird, Coleen P.; Hardman, Joel G.; Sutherland, Earl W.; Newman, Edwin B.

doi:10.1111/j.1749-6632.1971.tb45243.x

Cited by 85 publications

(53 citation statements)

References 11 publications

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“…The conservation of the majority residues for the IBMX binding agrees in general with the biochemical studies that IBMX is a nonselective inhibitor for various PDEs (44). The extra hydrogen bond between O-6 of IBMX and Gln-817 of PDE5A1 may account for the slightly higher potency of IBMX in PDE5 (IC 50 ϭ 10 M) (45) than that in PDE4 (IC 50 ϭ 31 M) (46).…”

Section: Resultssupporting

confidence: 70%

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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Section: Resultssupporting

confidence: 70%

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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“…Caffeine is a relatively non-selective agent and causes many effects in cells. For example, caffeine inhibits the nucleotide exchange activity of RCC1 (26), alkaline phosphatase activity (27), and phosphodiesterase activity (28,29).…”

mentioning

confidence: 99%

Caffeine Inhibits Checkpoint Responses without Inhibiting the Ataxia-Telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) Protein Kinases

Chen

2003

Journal of Biological Chemistry

138

103

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The ataxia-telangiectasia-mutated (ATM) and ATMand Rad3-related (ATR) kinases regulate cell cycle checkpoints by phosphorylating multiple substrates including the CHK1 and -2 protein kinases and p53. Caffeine has been widely used to study ATM and ATR signaling because it inhibits these kinases in vitro and overcomes cell cycle checkpoint responses in vivo. Thus, caffeine has been thought to overcome the checkpoint through its ability to prevent phosphorylation of ATM and ATR substrates. Surprisingly, I have found that multiple ATM-ATR substrates including CHK1 and -2 are hyperphosphorylated in cells treated with caffeine and genotoxic agents such as hydroxyurea or ionizing radiation. ATM autophosphorylation in cells is also increased when caffeine is used in combination with inhibitors of replication suggesting that ATM activity is not inhibited in vivo by caffeine. Furthermore, CHK1 hyperphosphorylation induced by caffeine in combination with hydroxyurea is ATR-dependent suggesting that ATR activity is stimulated by caffeine. Finally, the G 2 /M checkpoint in response to ionizing radiation or hydroxyurea is abrogated by caffeine treatment without a corresponding decrease in ATM-ATR-dependent signaling. This data suggests that although caffeine is an inhibitor of ATM-ATR kinase activity in vitro, it can block checkpoints without inhibiting ATM-ATR activation in vivo.

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“…This action is closely similar to that reported for phosphodiesterase inhibitors at other sympathetic neuro-effector junctions (cat spleen: Cubbedu et al, 1974;guinea-pig vas deferens: Stjarne et al, 1979). The evidence that this facilitation is a consequence of accumulation of cyclic AMP at an intracellular site is largely indirect, based on extrapolation of known actions of similar or higher concentrations of these phosphodiesterase inhibitors at other sites (Beavo, Rogers, Crofford, Hardman, Sutherland, Newman, 1970;Hamprecht & Schultz, 1973;Schofield & McPherson, 1974 (Shaw, Turnbull, Dutta, Gormley, Hayward & Stacey, 1978). Its ability to inhibit transmitter release was unaltered by the combination of IBMX and db cyclic AMP.…”

Section: Discussionmentioning

confidence: 99%

A Study of the Role of Cyclic Adenosine 3′,5′‐monophosphate in the Depression by Opiates and Opioid Peptides of Excitatory Junction Potentials in the Mouse Vas Deferens

North¹,

Vítek²

1980

British J Pharmacology

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I Excitatory junction potentials (ej.ps) were recorded with intracellular microelectrodes from smooth muscle cells of the mouse isolated vas deferens. The amplitude of the ej.p. was used as a measure of transmitter release evoked by applying single pulse stimuli to the intramural nerves. 2 Cyclic adenosine 3',5'-monophosphate (cyclic AMP) and dibutyryl cyclic AMP (db cyclic AMP, up to I mM) depressed the amplitude of ej.ps, probably by interacting with extracellular sites on the nerve terminals, similar to those responsive to adenosine.3 The phosphodiesterase inhibitors, 1-methyl-3-isobutyl xanthine (IBMX) and l-ethyl-4-hydrazino-1H-pyrazolo(3,4-b)pyridine-5-carboxylic acid, ethylester, hydrochloride (SQ20,006) increased ej.p. amplitude; this increase was much greater when the phosphodiesterase inhibitor was applied together with db cyclic AMP. 4 Neither the cyclic nucleotides nor the phosphodiesterase inhibitors altered the resting membrane potential of smooth muscle cells.5 The amplitude of the e.j.p. was depressed by normorphine, D-Ala2-Met5-enkephalinamide (DAEA) and D-Ala2-D-Leu5-enkephalin (DADL) with respective EC50s of 560 nM, 49 nm and 510 pM. 6 There was no change in the EC50 for normorphine in the presence of cyclic AMP (1 mM) or in the presence of a combination of IBMX (50 gM) and db cyclic AMP (500 gM). Similarly, the depression of the ej.p. by DAEA or DADL was not affected by the combination IBMX (500 gM) and db cyclic AMP (250 gM).7 These findings provide evidence against the hypothesis that a reduction in cyclic AMP levels in nerve terminals is an essential step in the inhibition by opiates and opioid peptides of transmitter release.

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Effects of Phosphodiesterase Inhibitors on Cyclic Amp Levels and on Lipolysis*

Cited by 85 publications

References 11 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

Caffeine Inhibits Checkpoint Responses without Inhibiting the Ataxia-Telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) Protein Kinases

A Study of the Role of Cyclic Adenosine 3′,5′‐monophosphate in the Depression by Opiates and Opioid Peptides of Excitatory Junction Potentials in the Mouse Vas Deferens

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