Cyclic nucleotide analogs as biochemical tools and prospective drugs

Schwede, Frank; Maronde, Erik; Genieser, Hans‐Gottfried; Jastorff, Bernd

doi:10.1016/s0163-7258(00)00051-6

Cited by 232 publications

(237 citation statements)

References 280 publications

Supporting

Mentioning

228

Contrasting

Unclassified

Order By: Relevance

“…Such a hypothesis is consistent with observations by Klamer et al (2005) who reported a correlation between increased extracellular cAMP levels in the hippocampus and PCPinduced PPI deficits. Extrusion of cAMP is likely to decrease intracellular signaling because cAMP is not membrane permeable (Schwede et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

Sensorimotor gating, the ability to automatically filter sensory information, is deficient in a number of psychiatric disorders, yet little is known of the biochemical mechanisms underlying this critical neural process. Previously, we reported that mice expressing a constitutively active isoform of the G-protein subunit Gas (Gas*) within forebrain neurons exhibit decreased gating, as measured by prepulse inhibition of acoustic startle (PPI). Here, to elucidate the biochemistry regulating sensorimotor gating and to identify novel therapeutic targets, we test the hypothesis that Gas* causes PPI deficits via brain region-specific changes in cyclic AMP (cAMP) signaling. As predicted from its ability to stimulate adenylyl cyclase, we find here that Gas* increases cAMP levels in the striatum. Suprisingly, however, Gas* mice exhibit reduced cAMP levels in the cortex and hippocampus because of increased cAMP phosphodiesterase (cPDE) activity. It is this decrease in cAMP that appears to mediate the effect of Gas* on PPI because Rp-cAMPS decreases PPI in C57BL/ 6J mice. Furthermore, the antipsychotic haloperidol increases both PPI and cAMP levels specifically in Gas* mice and the cPDE inhibitor rolipram also rescues PPI deficits of Gas* mice. Finally, to block potentially the pathway that leads to cPDE upregulation in Gas* mice, we coexpressed the R(AB) transgene (a dominant-negative regulatory subunit of protein kinase A (PKA)), which fully rescues the reductions in PPI and cAMP caused by Gas*. We conclude that expression of Gas* within forebrain neurons causes PPI deficits because of a PKAdependent decrease in cAMP and suggest that cAMP PDE inhibitors may exhibit antipsychotic-like therapeutic effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Kelly

Isiegas

Cheung

et al. 2006

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Consistently, the transfection of miR-142-3p inhibitor significantly increased intracellular cAMP levels and cytosolic PKA activity in primary T-leukemic cells and in T-leukemic cell lines ( Figures 4a and b); and transfection of miR-142-3p reduced levels of cAMP and PKA activity (Figures 4a and b). 8-BromocAMP and dibutyryl cAMP, cell-permeable cAMP analogs, are well known as the PKA activator; 25 Rp-cAMP, a diasteromer of cAMP, is a PKA inhibitor by competing with cAMP. 26 We found that the addition of either 8-bromo-cAMP or dibutyryl cAMP inhibited the promoting effect of miR-142-3p on T-leukemic cell proliferation ( Figure 4c); and addition of Rp-cAMP significantly attenuated the inhibitory effect of miR-142-3p inhibitor on T-leukemic cell proliferation (Figure 4d, Supplementary Figure 3).…”

Section: Mir-142-3p Promotes T-leukemic Cell Proliferation But Not Apmentioning

confidence: 99%

An oncogenic role of miR-142-3p in human T-cell acute lymphoblastic leukemia (T-ALL) by targeting glucocorticoid receptor-α and cAMP/PKA pathways

et al. 2011

View full text Add to dashboard Cite

“…The second class comprises molecules related to the endogenous PKA regulator, cAMP. 13 Cell permeable derivatives have been designed that either act as agonists (activating the holoenzyme in the same way as cAMP) or antagonists (competing with cAMP for binding to the R-subunit but not inducing holoenzyme dissociation).…”

Section: Pka Small Molecule Ligandsmentioning

confidence: 99%

“…Indeed, synthetic cAMP analogs have been designed that bind preferentially to one or the other site. 13 The most recent structure of a deletion mutant of type Iα R-subunit (containing A domain only) reveals major conformational changes in the A site upon binding to C-subunit 17 . This finding suggests that antagonists may be found that exploit the rearrangement of the A site between the holoenzyme (i.e.…”

Section: Targeting Pka Allosteric Sitesmentioning

confidence: 99%

Assay Principle for Modulators of Protein−Protein Interactions and Its Application to Non-ATP-Competitive Ligands Targeting Protein Kinase A

et al. 2006

View full text Add to dashboard Cite

Targeting sites that modulate protein-protein interactions represents an ongoing challenge for drug discovery. We have devised an assay principle, named Ligand-Regulated Competition (LiReC), in an effort to find non-ATP competitive small molecule regulators for type Iα cAMP-dependent Protein Kinase A (PKA-Iα), a protein complex that is implicated in disease. Our assay based on the LiReC principle utilizes a competitive fluorescent peptide probe to assess the integrity of the PKA-Iα complex upon introduction of an allosteric ligand. The developed fluorescence polarization method screens for small molecules that specifically protect (antagonists) or conversely activate (agonists) this protein complex. In high throughput format, various cyclic nucleotide-derived agonists and antagonists are successfully detected with high precision. Furthermore, assay performance (Z'-factors above 0.7) far exceeds the minimum requirement for small molecule screening. To identify compounds that operate through novel modes of action, our method shields the ATP binding site and purposely excludes ATP-competitive ligands. These proof-of-principle experiments highlight the potential of the LiReC technique and suggest its application to other protein complexes, thereby providing a novel approach to identify and characterize modulators (small molecules, proteins, peptides, or nucleic acids) of protein-protein systems.

show abstract

Cyclic nucleotide analogs as biochemical tools and prospective drugs

Cited by 232 publications

References 280 publications

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

Constitutive Activation of Gαs within Forebrain Neurons Causes Deficits in Sensorimotor Gating Because of PKA-Dependent Decreases in cAMP

An oncogenic role of miR-142-3p in human T-cell acute lymphoblastic leukemia (T-ALL) by targeting glucocorticoid receptor-α and cAMP/PKA pathways

Assay Principle for Modulators of Protein−Protein Interactions and Its Application to Non-ATP-Competitive Ligands Targeting Protein Kinase A

Contact Info

Product

Resources

About