8-Bromo-cAMP, sodium salt

8-Bromo-cAMP is a cAMP-analogues. [1]

cAMP can have an effect on the proliferative response of a cell. Either the effect is a positive or a negative regulator depending on the cell types. There is also variable effect of cAMP in hematopoietic cell lines. CAMP-analogues can significantly inhibit the erythropoietin-stimulated proliferation.[1]

8-Bromo-cAMP increased the cellular content of mRNA encoding the hCG a- and β-subunits and prevented the increase in fibronectin mRNA. This is determined by blot hybridization analysis using specific cDNA probes. 8-Bromo-cAMP also induced phosphorylation of Erk1,2 in AML193 cells. 8-Bromo-cAMP is an agent in AML193 cells and activates Erk1,2 , this condition happens does not accompanied by the involvement of Shc phosphorylation.[1,2]

8-bromo-cAMP increases catecholamine biosynthesis and produces an increase both in the activity and phosphorylation of tyrosine hydroxylase. 8-bromo-cAMP also promotes alterations in the synthesis and secretion of specific proteins, including fibronectin and the subunits of hCG by regulating mRNA expression.[2,3]

References:
[1]Ulloa-Aguirre A,?August AM,?etal. , 8-Bromo-adenosine?3',5'-monophosphate?regulates?expression?of?chorionic?gonadotropin?and fibronectin in human cytotrophoblasts. J Clin Endocrinol Metab.?1987 May;64(5):1002-9.
[2] Rene e M. Y. Barge, J.H. Frederik Falkenburg, etal., 8-Bromo-cAMP induces a proliferative response in an IL-3 dependent leukemic cell line and activates Erk1,2 via a Shc-independent pathway. Biochimica et Biophysica Acta 1355 (1997) 141–146.
[3] Haycock JW, Bennett WF, etal. , Multiple site phosphorylation of tyrosine hydroxylase. Differential regulation in situ by a 8-bromo-cAMP and acetylcholine. J Biol Chem. 1982 Nov 25;257(22):13699-703.

A cyclic AMP analog, 8-Br-cAMP, enhances the induction of pluripotency in human fibroblast cells.[Pubmed:21120637]

Stem Cell Rev. 2011 Jun;7(2):331-41.

Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by ectopic expression of four transcription factors. However, the efficiency of human iPS cell generation is extremely low and therefore elucidating the mechanisms underlying cellular reprogramming is of prime importance. We demonstrate that 8-Bromoadenosine 3', 5'-cyclic monophosphate (8-Br-cAMP) improves the reprogramming efficiency of human neonatal foreskin fibroblast (HFF1) cells transduced with the four transcription factors by 2-fold. The combination of 8-Br-cAMP and VPA synergistically increases the efficiency to 6.5-fold. The effect of 8-Br-cAMP or VPA may in part be due to the up-regulation of cytokine-related and inflammatory pathways. Remarkably, the synergistic effect of 8-Br-cAMP and VPA on cellular reprogramming may be due to the transient decrease of p53 protein during the early stages of reprogramming. However, it could also be due to additional differentially regulated genes and pathways such as the up-regulation of cytokine-related, inflammatory pathways and self-renewal supporting gene, namely cyclin-encoding CCND2, and the associated genes CCNA1 and CCNE1. Conversely, we also see the down-regulation of the p53 (CCNB2, GTSE1, SERPINE1) and cell cycle (PLK1, CCNB2) pathways. Our data demonstrates that a cyclic AMP analog, 8-Br-cAMP, enhances the efficiency of cellular reprogramming. In addition, 8-Br-cAMP and VPA have a synergistic effect on cellular reprogramming, which may be in part due to the transient down-regulation of the p53 signaling pathway during the early stages of reprogramming.

Protein kinase A induces recruitment of active Na+,K+-ATPase units to the plasma membrane of rat proximal convoluted tubule cells.[Pubmed:9679177]

J Physiol. 1998 Aug 15;511 ( Pt 1):235-43.

1. The aim of this study was to investigate the mechanism of control of Na+,K+-ATPase activity by the cAMP-protein kinase A (PKA) pathway in rat proximal convoluted tubules. For this purpose, we studied the in vitro action of exogenous cAMP (10-3 M dibutyryl-cAMP (db-cAMP) or 8-bromo-cAMP) and endogenous cAMP (direct activation of adenylyl cyclases by 10-5 M forskolin) on Na+,K+-ATPase activity and membrane trafficking. 2. PKA activation stimulated both the cation transport and hydrolytic activity of Na+,K+-ATPase by about 40%. Transport activity stimulation was specific to the PKA signalling pathway since (1) db-cAMP stimulated the ouabain-sensitive 86Rb+ uptake in a time- and dose-dependent fashion; (2) this effect was abolished by addition of H-89 or Rp-cAMPS, two structurally different PKA inhibitors; and (3) this stimulation was not affected by inhibition of protein kinase C (PKC) by GF109203X. The stimulatory effect of db-cAMP on the hydrolytic activity of Na+,K+-ATPase was accounted for by an increased maximal ATPase rate (Vmax) without alteration of the efficiency of the pump, suggesting that cAMP-PKA pathway was implicated in membrane redistribution control. 3. To test this hypothesis, we used two different approaches: (1) cell surface protein biotinylation and (2) subcellular fractionation. Both approaches confirmed that the cAMP-PKA pathway was implicated in membrane trafficking regulation. The stimulation of Na+,K+-ATPase activity by db-cAMP was associated with an increase (+40%) in Na+, K+-ATPase units expressed at the cell surface which was assessed by Western blotting after streptavidin precipitation of biotinylated cell surface proteins. Subcellular fractionation confirmed the increased expression in pump units at the cell surface which was accompanied by a decrease (-30%) in pump units located in the subcellular fraction corresponding to early endosomes. 4. In conclusion, PKA stimulates Na+,K+-ATPase activity, at least in part, by increasing the number of Na+-K+ pumps in the plasma membrane in proximal convoluted tubule cells.

Functional modulation of P2X2 receptors by cyclic AMP-dependent protein kinase.[Pubmed:9603227]

J Neurochem. 1998 Jun;70(6):2606-12.

It is generally believed that protein phosphorylation is an important mechanism through which the functions of voltage- and ligand-gated channels are modulated. The intracellular carboxyl terminus of P2X2 receptor contains several consensus phosphorylation sites for cyclic AMP (cAMP)-dependent protein kinase (PKA) and protein kinase C (PKC), suggesting that the function of the P2X2 purinoceptor could be regulated by the protein phosphorylation. Whole-cell voltage-clamp recording was used to record ATP-evoked cationic currents from human embryonic kidney (HEK) 293 cells stably transfected with the cDNA encoding the rat P2X2 receptor. Dialyzing HEK 293 cells with phorbol 12-myristate 13-acetate, a PKC activator, failed to affect the amplitude and kinetics of the ATP-induced cationic current. The role of PKA phosphorylation in modulating the function of the P2X2 receptor was investigated by internally perfusing HEK 293 cells with 8-bromo-cAMP or the purified catalytic subunit of PKA. Both 8-bromo-cAMP and PKA catalytic subunit caused a reduction in the magnitude of the ATP-activated current without affecting the inactivation kinetics and the value of reversal potential. Site-directed mutagenesis was also performed to replace the intracellular PKA consensus phosphorylation site (Ser431) with a cysteine residue. In HEK 293 cells expressing (S431C) mutant P2X2 receptors, intracellular perfusion of 8-bromo-cAMP or purified PKA catalytic subunit did not affect the amplitude of the ATP-evoked current. These results suggest that as with other ligand-gated ion channels, protein phosphorylation by PKA could play an important role in regulating the function of the P2X2 receptor and ATP-mediated physiological effects in the nervous system.

Lack of correlation between activation of cyclic AMP-dependent protein kinase and inhibition of contraction of rat vas deferens by cyclic AMP analogs.[Pubmed:1847496]

Mol Pharmacol. 1991 Feb;39(2):233-8.

The effects of N6,O2-dibutyrl-adenosine-3',5'-cyclic monophosphate (db-cAMP) and 8-bromo-adenosine-3',5'-cyclic monophosphate (8-Br-cAMP) on tension and cAMP-dependent protein kinase (PKA) activities in rat vas deferens were investigated. A soluble enzyme fraction obtained from the vas deferens was found to contain both type I and type II isozymes of PKA, whereas a particulate fraction contained only the type II isozyme. Exposure of the vas deferens to db-cAMP (1-100 microM) for 30 min caused a concentration-dependent inhibition of phenylephrine-induced contractions, with an EC50 of less than 10 microM. 8-Br-cAMP had no significant effect on contractions over a similar concentration range. Both of the analogs were able to activate PKA significantly at a concentration of 10 microM, and the magnitude of the PKA activation was greater with 8-Br-cAMP than with db-cAMP. Charcoal was added to the homogenization buffer in these experiments to prevent the artifactual activation of PKA by cAMP analogs trapped in the extracellular space. The ability of db-cAMP, but not 8-Br-cAMP, to inhibit the contraction of vas deferens could not be explained on the basis of differential activation of soluble or particulate PKA or of specific isozymes of the enzyme. It is, therefore, concluded that activation of PKA is not responsible for the relaxant effects of cAMP analogs in some smooth muscle.

8-Bromo-cAMP sodium salt (8-Br-Camp sodium salt), a cyclic AMP analog, is an activator of cyclic AMP-dependent protein kinase (PKA).

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