Basket (0 Items) - Amount: 0.00$cyclic AMP Signalling via Epac: Spotlight on a New Signal Transduction System
Hans-G. Genieser and Frank Schwede, BIOLOG Life Science Institute, Flughafendamm 9a, D-28199 Bremen, Germany
What is "Epac", actually?
The abbreviation Epac stands for exchange protein directly activated by cyclic AMP and describes a new type of receptor proteins for cyclic AMP, discovered only recently 1.
Up to now two different types, Epac 1 and Epac 2, can be distinguished, however, their tasks and importance are still elusive. In contrast to the protein kinase A (PKA) isozymes, Epac do not phosphorylate target proteins, but is a guanine exchange factor for the Ras-like small GTPases Rap1 and Rap2 (cAMP-GEF).
Numerous "classical" cyclic AMP/PKA systems need to be re-investigated re. Epac
With the discovery of the new receptor, in principle all well established cAMP systems need re-investigation in order to either reconfirm PKA as the only target, or to discover a more complex regulation system involving Epac alone or as a pathway separate or parallel to PKA. Corresponding investigations are done in many laboratories at the moment, and have already led to numerous surprising results and corresponding papers. Also, cases where a certain complexity of the cAMP signal transduction systems had been recognized but could not be further resolved, are now becoming transparent, and puzzle parts suddenly fall in place.
Epac is not just another exotic exception from PKA signalling, but is ubiquitiously expressed in numerous tissues. Epac has been found to play a role in the thyroid, in vascular permeability, skeletal muscle, kidney, ovary, ß-cells, adrenal gland, in certain brain functions and many more. Since research into this relatively new field has only recently begun, quite a lot of surprising results are still to be expected, allowing for a much more detailed insight in the already quite complex cyclic AMP signalling systems.
cAMP analogues with a methylated 2'-OH group can discriminate between Epac and PKA
In close collaboration with laboratories in Bergen and Utrecht, BIOLOG has developed a new class of Epac-specific compounds. These compounds are still analogues of cyclic AMP, however, their ribose 2’-hydroxy group has been methylated. Interestingly, this modification prevents from being recognized and accepted by PKA, but is, however, well tolerated by Epac.
- 8-CPT-2’-O-Me-cAMP
In case of the recently introduced 8-CPT-2'-O-Me-cAMP the resulting discrimination between both receptors is even three orders of magnitude. By means of this membrane-permeant analogue the participation of Epac has been proven in several biological systems for the first time.
N6- modified cAMP analogues are specific PKA agonists
On the other hand, also specific and potent activatiors of PKA are needed, that have no effect on Epac.
Unfortunately, most of the cyclic AMP analogues tested so far do not discriminate well between both receptors. Only structures that carry a modified 6 position at the adenine nucleobase were shown to be unable to activate Epac.
Thus, analogues such as N6-Benzoyl-cAMP or N6-Phenyl-cAMP, which were already in use as A-site preferring partners for synergistic activation of PKA, have now got unexpected new attention as PKA-specific agonists.
- 6-Bnz-cAMP
- 6-Phe-cAMP
Is there any activation of Epac with cGMP analogues?
No, there is’nt. As with N6-modified cyclic AMP analogues Epac does not tolerate the guanine nucleobase of cyclic GMP due to the oxygen modification at position 6 of the purine ring system. Thus, all established agonists and antagonists for protein kinase G, such as 8-Br-cGMP, 8-pCPT-cGMP, or Rp-8-Br-PET-cGMPS will not interfer with Epac.
Selected References:
- de Rooij, J. et al., Nature, 396, 474 (1998): "Epac is a Rap 1 Guanine-Nucleotide-Exchange Factor Directly Activated by Cyclic AMP"
- Enserink J.M.; Christensen, A.E.; de Rooij, J.; van Triest, M.; Schwede, F.; Genieser, H.-G.; Døskeland, S.O.; Blank, J.L.; Bos, J.L., Nature Cell Biol., 4, 901 (2002): “A novel Epac-specific cAMP Analog Demonstrates Independent Regulation of Rap1 and ERK“
- Kang, G.; Joseph, J.W.; Chepurny, O.G.; Monaco, M.; Wheeler, M.B.; Bos, J.L.; Schwede, F.; Genieser, H.-G.; Holz, G.G., J. Biol. Chem., 278, 8279 - 8285 (2003): "Epac-selective cAMP Analog 8-pCPT-2'-O-Me-cAMP as a Stimulus for Ca2+-induced Ca2+ Release and Exocytosis in Pancreatic beta-Cells"
- Christensen, A.E. et al., J. Biol. Chem., 278, 35394 (2003): "cAMP Analog Mapping of Epac1 and cAMP-Kinase. Discriminating Analogs Demonstrate that Epac and cAMP-Kinase Act Synergistically to Promote PC-12 Cell Neurite Extension"
- Kopperud, R. et al., FEBS Lett., 546, 121 (2003): "cAMP Effector Mechanisms. Novel Twists for an 'Old' Signaling System"
- Sakaba, T. and Neher, E., Nature, 424, 775 (2003): "Direct Modulation of Synaptic Vesicle Priming by GABA(B) Receptor Activation at a Glutamatergic Synapse"
- Bos, J.L., Nature Rev. Mol. Cell Biol., 4, 733 (2003): "Epac: A New cAMP Target and New Avenues in cAMP Research"
- Cullere, X. et al., Blood, 105, 1950 - 1955 (2005): “Regulation of Vascular Endothelial Barrier Function by Epac, a cAMP Activated Exchange Factor for Rap GTPase