cAMP, cGMP, cCMP and cUMP concentrations across the tree of life: High cCMP and cUMP levels in astrocytes

Hartwig, Christina; Bähre, Heike; Wolter, Sabine; Beckert, Ulrike; Kaever, Volkhard; Seifert, Roland

doi:10.1016/j.neulet.2014.07.019

Cited by 47 publications

(34 citation statements)

References 27 publications

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“…Technological advances in mass spectrometry have enabled molecular detection of pyrimidine cyclic nucleotides with relatively high sensitivity and specificity (9). Recently, a variety of cells and tissues have been shown to constitutively possess cUMP and cCMP (4,24). Mammalian soluble adenylyl and guanylyl cyclases are capable of synthesizing these cyclic nucleotides under some experimental conditions (3,25), and phosphodiesterase 3A and 3B degrade cUMP (47) while phosphodiesterase 7A1 inactivates cCMP (40).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Morrow

Seifert

Kaever

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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Section: Discussionmentioning

confidence: 99%

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Morrow

Seifert

Kaever

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…cCMP is synthesized by soluble adenylyl cyclase [4], by soluble guanylyl cyclase [6] and by the Pseudomonas aeruginosa exotoxin ExoY [7]. It occurs in numerous cell types like human embryonic kidney cell line (HEK-293) cells and rat B103 neuroblastoma cells and primary cells from the neuronal, mesenchymal or epithelial lineage [8]. The activity of hyperpolarization-activated cyclic nucleotidegated cation channel (HCN) ion channels is modulated by cCMP [9].…”

Section: Introductionmentioning

confidence: 99%

PDE7A1 hydrolyzes cCMP

et al. 2014

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a b s t r a c tThe degradation and biological role of the cyclic pyrimidine nucleotide cCMP is largely elusive. We investigated nucleoside 3 0 ,5 0 -cyclic monophosphate (cNMP) specificity of six different recombinant phosphodiesterases (PDEs) by using a highly-sensitive HPLC-MS/MS detection method. PDE7A1 was the only enzyme that hydrolyzed significant amounts of cCMP. Enzyme kinetic studies using purified GST-tagged truncated PDE7A1 revealed a cCMP K M value of 135 ± 19 lM. The V max for cCMP hydrolysis reached 745 ± 27 nmol/(min mg), which is about 6-fold higher than the corresponding velocity for adenosine 3 0 ,5 0 -cyclic monophosphate (cAMP) degradation. In summary, PDE7A is a high-speed and low-affinity PDE for cCMP.

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“…cCMP has been unequivocally identified in intact mammalian cells using the most sophisticated mass spectrometry methods (MS/MS and MS/TOF) currently available Bähre et al 2014;Hartwig et al 2014). Cellular cCMP concentrations can be quite high, e.g., in HEK293 cells basal cCMP has been conservatively estimated to be in the 30-μM range (Monzel et al 2014;Hartwig et al 2014). The soluble adenylyl cyclase is accountable for high basal cCMP concentrations in HEK293 cells and neuroblastoma cells (Hasan et al 2014).…”

Section: Introductionmentioning

confidence: 99%

N4-monobutyryl-cCMP activates PKA RIα and PKA RIIα more potently and with higher efficacy than PKG Iα in vitro but not in vivo

Wolter

Dove

Golombek

et al. 2014

Naunyn-Schmiedeberg's Arch Pharmacol

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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.

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cAMP, cGMP, cCMP and cUMP concentrations across the tree of life: High cCMP and cUMP levels in astrocytes

Cited by 47 publications

References 27 publications

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

Heterogeneity of pulmonary endothelial cyclic nucleotide response toPseudomonas aeruginosaExoY infection

PDE7A1 hydrolyzes cCMP

N4-monobutyryl-cCMP activates PKA RIα and PKA RIIα more potently and with higher efficacy than PKG Iα in vitro but not in vivo

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