Direct Activation of PDE5 by CGMP: Long-term Effects Within NO/cGMP Signaling

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2003 Feb 27

PMID 12604588

Citations 44

Authors

Florian Mullershausen

Andreas Friebe

Robert Feil

W Joseph Thompson

Franz Hofmann

Doris Koesling

Affiliations

Soon will be listed here.

Abstract

In platelets, the nitric oxide (NO)-induced cGMP response is indicative of a highly regulated interplay of cGMP formation and cGMP degradation. Recently, we showed that within the NO-induced cGMP response in human platelets, activation and phosphorylation of phosphodiesterase type 5 (PDE5) occurred. Here, we identify cyclic GMP-dependent protein kinase I as the kinase responsible for the NO-induced PDE5 phosphorylation. However, we demonstrate that cGMP can directly activate PDE5 without phosphorylation in platelet cytosol, most likely via binding to the regulatory GAF domains. The reversal of activation was slow, and was not completed after 60 min. Phosphorylation enhanced the cGMP-induced activation, allowing it to occur at lower cGMP concentrations. Also, in intact platelets, a sustained NO-induced activation of PDE5 for as long as 60 min was detected. Finally, the long-term desensitization of the cGMP response induced by a low NO concentration reveals the physiological relevance of the PDE5 activation within NO/cGMP signaling. In sum, we suggest NO-induced activation and phosphorylation of PDE5 as the mechanism for a long-lasting negative feedback loop shaping the cGMP response in human platelets in order to adapt to the amount of NO available.

Citing Articles

Pathophysiology of Preeclampsia and L-Arginine/L-Citrulline Supplementation as a Potential Strategy to Improve Birth Outcomes.

Ortiz-Cerda T, Mosso C, Alcudia A, Vazquez-Roman V, Gonzalez-Ortiz M Adv Exp Med Biol. 2023; 1428:127-148.

PMID: 37466772 DOI: 10.1007/978-3-031-32554-0_6.

Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors.

Ovchinnikov A, Potekhina A, Belyavskiy E, Ageev F Pharmaceuticals (Basel). 2022; 15(8).

PMID: 36015172 PMC: 9414416. DOI: 10.3390/ph15081024.

Phosphodiesterase-5 Inhibitor Attenuates Anxious Phenotypes and Movement Disorder Induced by Mild Ischemic Stroke in Rats.

Yu Y, Kim S, Kang J, Song Y, Im H, Kim S J Korean Neurosurg Soc. 2022; 65(5):665-679.

PMID: 35430790 PMC: 9452378. DOI: 10.3340/jkns.2021.0101.

Protective and therapeutic effects of sildenafil and tadalafil on aflatoxin B1-induced hepatocellular carcinoma.

Chhonker S, Rawat D, Koiri R Mol Cell Biochem. 2020; 476(2):1195-1209.

PMID: 33216253 DOI: 10.1007/s11010-020-03982-6.

Preeclampsia beyond pregnancy: long-term consequences for mother and child.

Turbeville H, Sasser J Am J Physiol Renal Physiol. 2020; 318(6):F1315-F1326.

PMID: 32249616 PMC: 7311709. DOI: 10.1152/ajprenal.00071.2020.

References

Wyatt T, Naftilan A, Francis S, Corbin J . ANF elicits phosphorylation of the cGMP phosphodiesterase in vascular smooth muscle cells. Am J Physiol. 1998; 274(2):H448-55. DOI: 10.1152/ajpheart.1998.274.2.H448. View

Turko I, Francis S, Corbin J . Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. Biochem J. 1998; 329 ( Pt 3):505-10. PMC: 1219070. DOI: 10.1042/bj3290505. View

Koesling D, Friebe A . Soluble guanylyl cyclase: structure and regulation. Rev Physiol Biochem Pharmacol. 1999; 135:41-65. DOI: 10.1007/BFb0033669. View

Juilfs D, Soderling S, Burns F, Beavo J . Cyclic GMP as substrate and regulator of cyclic nucleotide phosphodiesterases (PDEs). Rev Physiol Biochem Pharmacol. 1999; 135:67-104. DOI: 10.1007/BFb0033670. View

Biel M, Zong X, Ludwig A, Sautter A, Hofmann F . Structure and function of cyclic nucleotide-gated channels. Rev Physiol Biochem Pharmacol. 1999; 135:151-71. DOI: 10.1007/BFb0033672. View

Corbin J, Francis S . Cyclic GMP phosphodiesterase-5: target of sildenafil. J Biol Chem. 1999; 274(20):13729-32. DOI: 10.1074/jbc.274.20.13729. View

Hofmann F, Ammendola A, Schlossmann J . Rising behind NO: cGMP-dependent protein kinases. J Cell Sci. 2000; 113 ( Pt 10):1671-6. DOI: 10.1242/jcs.113.10.1671. View

Corbin J, Turko I, Beasley A, Francis S . Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem. 2000; 267(9):2760-7. DOI: 10.1046/j.1432-1327.2000.01297.x. View

Francis S, Turko I, Corbin J . Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol. 2000; 65:1-52. DOI: 10.1016/s0079-6603(00)65001-8. View

10.

Mullershausen F, Russwurm M, Thompson W, Liu L, Koesling D, Friebe A . Rapid nitric oxide-induced desensitization of the cGMP response is caused by increased activity of phosphodiesterase type 5 paralleled by phosphorylation of the enzyme. J Cell Biol. 2001; 155(2):271-8. PMC: 2198829. DOI: 10.1083/jcb.200107001. View

11.

Schwarz U, Walter U, Eigenthaler M . Taming platelets with cyclic nucleotides. Biochem Pharmacol. 2001; 62(9):1153-61. DOI: 10.1016/s0006-2952(01)00760-2. View

12.

Liu L, Underwood T, Li H, Pamukcu R, Thompson W . Specific cGMP binding by the cGMP binding domains of cGMP-binding cGMP specific phosphodiesterase. Cell Signal. 2001; 14(1):45-51. DOI: 10.1016/s0898-6568(01)00216-9. View

13.

Wegener J, Nawrath H, Wolfsgruber W, Kuhbandner S, Werner C, Hofmann F . cGMP-dependent protein kinase I mediates the negative inotropic effect of cGMP in the murine myocardium. Circ Res. 2002; 90(1):18-20. DOI: 10.1161/hh0102.103222. View

14.

Rybalkin S, Rybalkina I, Feil R, Hofmann F, Beavo J . Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem. 2001; 277(5):3310-7. DOI: 10.1074/jbc.M106562200. View

15.

Kanacher T, Schultz A, Linder J, Schultz J . A GAF-domain-regulated adenylyl cyclase from Anabaena is a self-activating cAMP switch. EMBO J. 2002; 21(14):3672-80. PMC: 126120. DOI: 10.1093/emboj/cdf375. View

16.

Rybalkin S, Rybalkina I, Shimizu-Albergine M, Tang X, Beavo J . PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J. 2003; 22(3):469-78. PMC: 140735. DOI: 10.1093/emboj/cdg051. View

17.

Martins T, Mumby M, Beavo J . Purification and characterization of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. J Biol Chem. 1982; 257(4):1973-9. View

18.

Ogreid D, Ekanger R, Suva R, Miller J, Sturm P, Corbin J . Activation of protein kinase isozymes by cyclic nucleotide analogs used singly or in combination. Principles for optimizing the isozyme specificity of analog combinations. Eur J Biochem. 1985; 150(1):219-27. DOI: 10.1111/j.1432-1033.1985.tb09010.x. View

19.

Humbert P, Niroomand F, Fischer G, Mayer B, Koesling D, Hinsch K . Purification of soluble guanylyl cyclase from bovine lung by a new immunoaffinity chromatographic method. Eur J Biochem. 1990; 190(2):273-8. DOI: 10.1111/j.1432-1033.1990.tb15572.x. View

20.

Lohmann S, Vaandrager A, Smolenski A, Walter U, de Jonge H . Distinct and specific functions of cGMP-dependent protein kinases. Trends Biochem Sci. 1997; 22(8):307-12. DOI: 10.1016/s0968-0004(97)01086-4. View