| Dokumentenart: | Artikel | ||||||||||||||||||||||||||||
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| Titel eines Journals oder einer Zeitschrift: | Naunyn-Schmiedeberg's archives of pharmacology | ||||||||||||||||||||||||||||
| Verlag: | Springer | ||||||||||||||||||||||||||||
| Band: | 387 | ||||||||||||||||||||||||||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 12 | ||||||||||||||||||||||||||||
| Seitenbereich: | S. 1163-1175 | ||||||||||||||||||||||||||||
| Datum: | 2014 | ||||||||||||||||||||||||||||
| Institutionen: | Chemie und Pharmazie > Institut für Pharmazie > Lehrstuhl Pharmazeutische / Medizinische Chemie II (Prof. Buschauer) | ||||||||||||||||||||||||||||
| Identifikationsnummer: |
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| Stichwörter / Keywords: | cAMP-dependent protein kinase cGMP-dependent protein kinase Cyclic CMP Dibutyryl-cCMP N4-monobutyryl-cCMP | ||||||||||||||||||||||||||||
| Dewey-Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie 600 Technik, Medizin, angewandte Wissenschaften > 615 Pharmazie | ||||||||||||||||||||||||||||
| Status: | Veröffentlicht | ||||||||||||||||||||||||||||
| Begutachtet: | Ja, diese Version wurde begutachtet | ||||||||||||||||||||||||||||
| An der Universität Regensburg entstanden: | Zum Teil | ||||||||||||||||||||||||||||
| Dokumenten-ID: | 33097 |
Zusammenfassung
There is increasing evidence for a role of cytidine 3',5'-cyclic monophosphate (cCMP) as second messenger. In a recent study, we showed that cCMP activates both purified guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase Iα (PKG Iα) and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) isoenzymes with the regulatory subunits RIα and RIIα. Moreover, the ...
Zusammenfassung
There is increasing evidence for a role of cytidine 3',5'-cyclic monophosphate (cCMP) as second messenger. In a recent study, we showed that cCMP activates both purified guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase Iα (PKG Iα) and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) isoenzymes with the regulatory subunits RIα and RIIα. Moreover, the membrane-permeant cCMP analog dibutyryl (DB)-cCMP induces effective vasodilation and inhibition of platelet aggregation via PKG Iα, but not via PKA. These data prompted us to conduct a systematic analysis of the effects of cyclic nucleotide (cNMP) analogs on purified PKG Iα and PKA RIα and RIIα We also studied the effect of DB-cCMP on PKA-dependent phosphorylation of the transcription factor cAMP response-binding protein (CREB) in S49 wild-type lymphoma cells and S49 kin(-) cells, devoid of the catalytic subunit of PKA. The major cellular metabolite of the prodrug DB-cCMP, N(4)-monobutyryl (4-MB)-cCMP, was a partial and low-potency activator of purified PKG Iα and a full and moderate-potency activator of PKA RIα and RIIα. Sp-cCMPS and Sp-cAMPS activated PKA RIα and RIIα with much higher potency and efficacy than PKG Iα. Molecular modeling suggested that the cytidine ring interacts with PKG Iα mainly via hydrophobic interactions, while the butyryl group projects away from the kinase. In contrast to DB-cAMP, DB-cCMP did not induce PKA-dependent phosphorylation in intact cells. Taken together, our data show that N(4)-monobutyryl-cCMP (4-MB-cCMP) activates PKA RIα and PKA RIIα more potently and with higher efficacy than PKG Iα in vitro but not in vivo. cNMP phosphorothioates constitute a starting point for the development of PKA activators with high selectivity relative to PKG.
Metadaten zuletzt geändert: 29 Sep 2021 07:40
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