title: cNMP-AMs mimic and dissect bacterial nucleotidyl cyclase toxin effects.
abstract: In addition to the well-known second messengers cAMP and cGMP, mammalian cells contain the cyclic pyrimidine nucleotides cCMP and cUMP. The Pseudomonas aeruginosa toxin ExoY massively increases cGMP and cUMP in cells, whereas the Bordetella pertussis toxin CyaA increases cAMP and, to a lesser extent, cCMP. To mimic and dissect toxin effects, we synthesized cNMP-acetoxymethylesters as prodrugs. cNMP-AMs rapidly and effectively released the corresponding cNMP in cells. The combination of cGMP-AM plus cUMP-AM mimicked cytotoxicity of ExoY. cUMP-AM and cGMP-AM differentially activated gene expression. Certain cCMP and cUMP effects were independent of the known cNMP effectors protein kinases A and G and guanine nucleotide exchange factor Epac. In conclusion, cNMP-AMs are useful tools to mimic and dissect bacterial nucleotidyl cyclase toxin effects.
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: beckert-ulrike81@email.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Beckert
authors.affiliation: Institute of Pharmaceutical Biology, Nussallee 6, D-53115 Bonn, Germany. Electronic address: grundmann@uni-bonn.de.
authors.forename: Manuel
authors.initials: M
authors.lastname: Grundmann
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: wolter.sabine@mh-hannover.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wolter
authors.affiliation: Biolog Life Science Institute, Flughafendamm 9a, D-28199 Bremen, Germany. Electronic address: fs@biolog.de.
authors.forename: Frank
authors.initials: F
authors.lastname: Schwede
authors.affiliation: Molecular Cancer Research, University Medical Center Utrecht, Universiteitsweg 100, NL-3584 Utrecht, The Netherlands. Electronic address: h.rehmann@UMCutrecht.nl.
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
authors.affiliation: Core Unit Metabolomics, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: kaever.volkhard@mh-hannover.de.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
authors.affiliation: Institute of Pharmaceutical Biology, Nussallee 6, D-53115 Bonn, Germany. Electronic address: kostenis@uni-bonn.de.
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: seifert.roland@mh-hannover.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D037361:Adenylate Cyclase Toxin / Q000494:pharmacology; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D001427:Bacterial Toxins / Q000494:pharmacology*; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D005964:Glucosyltransferases / Q000494:pharmacology; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D051381:Rats; D015290:Second Messenger Systems / Q000502:physiology; D014407:Tumor Cells, Cultured; D014542:Uridine Monophosphate / Q000494:pharmacology*
chemical_list: D037361:Adenylate Cyclase Toxin; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D009712:Nucleotides, Cyclic; C045338:cyclic 3',5'-uridine monophosphate; D014542:Uridine Monophosphate; C111504:ExoY protein, bacteria; D005964:Glucosyltransferases; D006152:Cyclic GMP
keywords: Dynamic mass distribution; Gene expression; Prodrug; cCMP; cNMP-AM; cUMP