Abstract
cCMP and cUMP are pyrimidine cyclic nucleotides which are present in several types of cells. These molecules could exert diverse cellular functions and might act as second messengers. In the last years, diverse approaches were performed to analyze possible cellular substrates and signaling pathways of cCMP and cUMP. In this review these approaches are summarized, and probable cross talk of these signaling molecules is described. These analyses might lead to the (patho)physiological and pharmacological relevance of these noncanonical cyclic nucleotides.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- cCMP:
-
Cyclic cytidine monophosphate
- cUMP:
-
Cyclic uridine monophosphate
- MS:
-
Mass spectrometry
- PDEs:
-
Phosphodiesterases
- PKA:
-
cAMP-dependent protein kinase
- PKG:
-
cGMP-dependent protein kinase
References
Akimoto M, Zhang Z, Boulton S, Selvaratnam R, VanSchouwen B, Gloyd M, Accili EA, Lange OF, Melacini G (2014) A mechanism for the auto-inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel opening and its relief by cAMP. J Biol Chem 289:22205–22220
Al-Shboul O, Mahavadi S, Sriwai W, Grider JR, Murthy KS (2013) Differential expression of multidrug resistance protein 5 and phosphodiesterase 5 and regulation of cGMP levels in phasic and tonic smooth muscle. Am J Physiol Gastrointest Liver Physiol 305:G314–G324
Aronsen L, Orvoll E, Lysaa R, Ravna AW, Sager G (2014) Modulation of high affinity ATP-dependent cyclic nucleotide transporters by specific and non-specific cyclic nucleotide phosphodiesterase inhibitors. Eur J Pharmacol 745:249–253
Aye TT, Mohammed S, van den Toorn HW, van Veen TA, van der Heyden MA, Scholten A, Heck AJ (2009) Selectivity in enrichment of cAMP-dependent protein kinase regulatory subunits type I and type II and their interactors using modified cAMP affinity resins. Mol Cell Proteomics 8:1016–1028
Bähre H, Danker KY, Stasch JP, Kaever V, Seifert R (2014) Nucleotidyl cyclase activity of soluble guanylyl cyclase in intact cells. Biochem Biophys Res Commun 443:1195–1199
Bähre H, Hartwig C, Munder A, Wolter S, Stelzer T, Schirmer B, Beckert U, Frank DW, Tummler B, Kaever V, Seifert R (2015) cCMP and cUMP occur in vivo. Biochem Biophys Res Commun 460:909–914
Beckert U, Grundmann M, Wolter S, Schwede F, Rehmann H, Kaever V, Kostenis E, Seifert R (2014a) cNMP-AMs mimic and dissect bacterial nucleotidyl cyclase toxin effects. Biochem Biophys Res Commun 451:497–502
Beckert U, Wolter S, Hartwig C, Bähre H, Kaever V, Ladant D, Frank DW, Seifert R (2014b) ExoY from Pseudomonas aeruginosa is a nucleotidyl cyclase with preference for cGMP and cUMP formation. Biochem Biophys Res Commun 450:870–874
Beste KY, Burhenne H, Kaever V, Stasch JP, Seifert R (2012) Nucleotidyl cyclase activity of soluble guanylyl cyclase alpha1beta1. Biochemistry 51:194–204
Bond AE, Dudley E, Tuytten R, Lemiere F, Smith CJ, Esmans EL, Newton RP (2007) Mass spectrometric identification of Rab23 phosphorylation as a response to challenge by cytidine 3′,5′-cyclic monophosphate in mouse brain. Rapid Commun Mass Spectrom 21:2685–2692
Browning DD, Windes ND, Ye RD (1999) Activation of p38 mitogen-activated protein kinase by lipopolysaccharide in human neutrophils requires nitric oxide-dependent cGMP accumulation. J Biol Chem 274:537–542
Browning DD, McShane MP, Marty C, Ye RD (2000) Nitric oxide activation of p38 mitogen-activated protein kinase in 293T fibroblasts requires cGMP-dependent protein kinase. J Biol Chem 275:2811–2816
Corrie JE, Pizza C, Makwana J, King RW (1992) Preparation and properties of an affinity support for purification of cyclic AMP receptor protein from Escherichia coli. Protein Expr Purif 3:417–420
Dalvit C, Flocco M, Knapp S, Mostardini M, Perego R, Stockman BJ, Veronesi M, Varasi M (2002) High-throughput NMR-based screening with competition binding experiments. J Am Chem Soc 124:7702–7709
Desch M, Schinner E, Kees F, Hofmann F, Seifert R, Schlossmann J (2010) Cyclic cytidine 3′,5′-monophosphate (cCMP) signals via cGMP kinase I. FEBS Lett 584:3979–3984
Fila J, Honys D (2012) Enrichment techniques employed in phosphoproteomics. Amino Acids 43:1025–1047
Fischer JJ, Graebner O, Dreger M, Glinski M, Baumgart S, Koester H (2011) Improvement of capture compound mass spectrometry technology (CCMS) for the profiling of human kinases by combination with 2D LC-MS/MS. J Biomed Biotechnol 2011:850589
Gottle M, Dove S, Kees F, Schlossmann J, Geduhn J, Konig B, Shen Y, Tang WJ, Kaever V, Seifert R (2010) Cytidylyl and uridylyl cyclase activity of Bacillus anthracis edema factor and Bordetella pertussis CyaA. Biochemistry 49:5494–5503
Hammerschmidt A, Chatterji B, Zeiser J, Schroder A, Genieser HG, Pich A, Kaever V, Schwede F, Wolter S, Seifert R (2012) Binding of regulatory subunits of cyclic AMP-dependent protein kinase to cyclic CMP agarose. PLoS One 7, e39848
Hanke SE, Bertinetti D, Badel A, Schweinsberg S, Genieser HG, Herberg FW (2010) Cyclic nucleotides as affinity tools: phosphorothioate cAMP analogues address specific PKA subproteomes. N Biotechnol 28:294–301
Hanke SE, Bertinetti D, Badel A, Schweinsberg S, Genieser HG, Herberg FW (2011) Cyclic nucleotides as affinity tools: phosphorothioate cAMP analogues address specific PKA subproteomes. N Biotechnol 28:294–301
Hardman JG, Robison GA, Sutherland EW (1971) Cyclic nucleotides. Annu Rev Physiol 33:311–336
Hartwig C, Bähre H, Wolter S, Beckert U, Kaever V, Seifert R (2014) cAMP, cGMP, cCMP and cUMP concentrations across the tree of life: high cCMP and cUMP levels in astrocytes. Neurosci Lett 579:183–187
Hasan A, Danker KY, Wolter S, Bähre H, Kaever V, Seifert R (2014) Soluble adenylyl cyclase accounts for high basal cCMP and cUMP concentrations in HEK293 and B103 cells. Biochem Biophys Res Commun 448:236–240
Jiang L, Lan T, Chen Y, Sang J, Li Y, Wu M, Tao Y, Wang Y, Qian H, Gu L (2013) PKG II inhibits EGF/EGFR-induced migration of gastric cancer cells. PLoS One 8, e61674
Karakhanova S, Golovastova M, Philippov PP, Werner J, Bazhin AV (2014) Interlude of cGMP and cGMP/protein kinase G type 1 in pancreatic adenocarcinoma cells. Pancreas 43:784–794
Kerenyi L, Gallyas F (1972) A highly sensitive method for demonstrating proteins in electrophoretic, immunoelectrophoretic and immunodiffusion preparations. Clin Chim Acta 38:465–467
Koller A, Schlossmann J, Ashman K, Uttenweiler-Joseph S, Ruth P, Hofmann F (2003) Association of phospholamban with a cGMP kinase signaling complex. Biochem Biophys Res Commun 300:155–160
Koster H, Little DP, Luan P, Muller R, Siddiqi SM, Marappan S, Yip P (2007) Capture compound mass spectrometry: a technology for the investigation of small molecule protein interactions. Assay Drug Dev Technol 5:381–390
Laue S, Winterhoff M, Kaever V, van den Heuvel JJ, Russel FG, Seifert R (2014) cCMP is a substrate for MRP5. Naunyn Schmiedebergs Arch Pharmacol 387:893–895
Luo Y, Blex C, Baessler O, Glinski M, Dreger M, Sefkow M, Koster H (2009) The cAMP capture compound mass spectrometry as a novel tool for targeting cAMP-binding proteins: from protein kinase A to potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channels. Mol Cell Proteomics 8:2843–2856
Mayer M, Meyer B (2001) Group epitope mapping by saturation transfer difference NMR to identify segments of a ligand in direct contact with a protein receptor. J Am Chem Soc 123:6108–6117
Monzel M, Kuhn M, Bähre H, Seifert R, Schneider EH (2014) PDE7A1 hydrolyzes cCMP. FEBS Lett 588:3469–3474
Nesper J, Reinders A, Glatter T, Schmidt A, Jenal U (2012) A novel capture compound for the identification and analysis of cyclic di-GMP binding proteins. J Proteomics 75:4874–4878
Newton RP, Salih SG, Salvage BJ, Kingston EE (1984) Extraction, purification and identification of cytidine 3′,5′-cyclic monophosphate from rat tissues. Biochem J 221:665–673
Oeckl P, Ferger B (2012) Simultaneous LC-MS/MS analysis of the biomarkers cAMP and cGMP in plasma, CSF and brain tissue. J Neurosci Methods 203:338–343
Pfeifer A, Ruth P, Dostmann W, Sausbier M, Klatt P, Hofmann F (1999) Structure and function of cGMP-dependent protein kinases. Rev Physiol Biochem Pharmacol 135:105–149
Reinecke D, Burhenne H, Sandner P, Kaever V, Seifert R (2011) Human cyclic nucleotide phosphodiesterases possess a much broader substrate-specificity than previously appreciated. FEBS Lett 585:3259–3262
Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P (2000) Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature 404:197–201
Schneider EH, Seifert R (2015) Report on the third symposium “cCMP and cUMP as New second messengers”. Naunyn Schmiedebergs Arch Pharmacol 388:1–3
Schultz C, Vajanaphanich M, Genieser HG, Jastorff B, Barrett KE, Tsien RY (1994) Membrane-permeant derivatives of cyclic AMP optimized for high potency, prolonged activity, or rapid reversibility. Mol Pharmacol 46:702–708
Schwede F, Maronde E, Genieser H, Jastorff B (2000) Cyclic nucleotide analogs as biochemical tools and prospective drugs. Pharmacol Ther 87:199–226
Seifert R (2015) cCMP and cUMP: emerging second messengers. Trends Biochem Sci 40:8–15
Seifert R, Schneider EH, Bähre H (2015) From canonical to non-canonical cyclic nucleotides as second messengers: pharmacological implications. Pharmacol Ther 148:154–184
Stork PJ, Schmitt JM (2002) Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 12:258–266
Vossler MR, Yao H, York RD, Pan MG, Rim CS, Stork PJ (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89:73–82
Weiss W, Weiland F, Gorg A (2009) Protein detection and quantitation technologies for gel-based proteome analysis. Methods Mol Biol 564:59–82
Wielinga PR, van der Heijden I, Reid G, Beijnen JH, Wijnholds J, Borst P (2003) Characterization of the MRP4- and MRP5-mediated transport of cyclic nucleotides from intact cells. J Biol Chem 278:17664–17671
Witters E, Van Dongen W, Esmans EL, Van Onckelen HA (1997) Ion-pair liquid chromatography-electrospray mass spectrometry for the analysis of cyclic nucleotides. J Chromatogr B Biomed Sci Appl 694:55–63
Wolfertstetter S, Reinders J, Schwede F, Ruth P, Schinner E, Schlossmann J (2015) Interaction of cCMP with the cGK, cAK and MAPK kinases in murine tissues. PLoS One 10, e0126057
Wolter S, Golombek M, Seifert R (2011) Differential activation of cAMP- and cGMP-dependent protein kinases by cyclic purine and pyrimidine nucleotides. Biochem Biophys Res Commun 415:563–566
Wolter S, Dove S, Golombek M, Schwede F, Seifert R (2014) N-monobutyryl-cCMP activates PKA RIalpha and PKA RIIalpha more potently and with higher efficacy than PKG ialpha in vitro but not in vivo. Naunyn Schmiedebergs Arch Pharmacol 387:1163–1175
Wolter S, Kloth C, Golombek M, Dittmar F, Forsterling L, Seifert R (2015) cCMP causes caspase-dependent apoptosis in mouse lymphoma cell lines. Biochem Pharmacol 98:119–131
Yao H, Sem DS (2005) Cofactor fingerprinting with STD NMR to characterize proteins of unknown function: identification of a rare cCMP cofactor preference. FEBS Lett 579:661–666
Zong X, Krause S, Chen CC, Kruger J, Gruner C, Cao-Ehlker X, Fenske S, Wahl-Schott C, Biel M (2012) Regulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity by cCMP. J Biol Chem 287:26506–26512
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Schlossmann, J., Wolfertstetter, S. (2015). Identification of cCMP and cUMP Substrate Proteins and Cross Talk Between cNMPs. In: Seifert, R. (eds) Non-canonical Cyclic Nucleotides. Handbook of Experimental Pharmacology, vol 238. Springer, Cham. https://doi.org/10.1007/164_2015_38
Download citation
DOI: https://doi.org/10.1007/164_2015_38
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-52671-3
Online ISBN: 978-3-319-52673-7
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)