Wolter, Sabine and Dove, Stefan and Golombek, Marina and Schwede, Frank and Seifert, Roland (2014) N-4-monobutyryl-cCMP activates PKA RI alpha and PKA RII alpha more potently and with higher efficacy than PKG I alpha in vitro but not in vivo. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 387 (12). pp. 1163-1175. ISSN 0028-1298, 1432-1912
Full text not available from this repository. (Request a copy)Abstract
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 I alpha (PKG I alpha) and adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) isoenzymes with the regulatory subunits RI alpha and RII alpha. Moreover, the membrane-permeant cCMP analog dibutyryl (DB)-cCMP induces effective vasodilation and inhibition of platelet aggregation via PKG I alpha, but not via PKA. These data prompted us to conduct a systematic analysis of the effects of cyclic nucleotide (cNMP) analogs on purified PKG I alpha and PKA RI alpha and RII alpha 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 I alpha and a full and moderate-potency activator of PKA RI alpha and RII alpha. Sp-cCMPS and Sp-cAMPS activated PKA RI alpha and RII alpha with much higher potency and efficacy than PKG I alpha. Molecular modeling suggested that the cytidine ring interacts with PKG I alpha 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 RI alpha and PKA RII alpha more potently and with higher efficacy than PKG I alpha in vitro but not in vivo. cNMP phosphorothioates constitute a starting point for the development of PKA activators with high selectivity relative to PKG.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NUCLEOTIDYL CYCLASE ACTIVITY; DEPENDENT PROTEIN-KINASES; SOLUBLE GUANYLYL CYCLASE; CUMP CONCENTRATIONS; CYCLIC-NUCLEOTIDES; CGMP; CELLS; CAMP; CCMP; ANALOGS; cAMP-dependent protein kinase; cGMP-dependent protein kinase; Cyclic CMP; Dibutyryl-cCMP; N-4-monobutyryl-cCMP |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Aug 2019 10:59 |
| Last Modified: | 07 Aug 2019 10:59 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9164 |
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