The function of AKAP-dependent protein-protein interactions in the regulation of vasopressin-mediated water reabsorption and cardiac myocyte contractility
Final Report Abstract
A-kinase anchoring proteins (AKAPs) are scaffolding proteins that directly interact with protein kinase A (PKA) and thereby spatially and temporally constrict PKA activity to defined cellular compartments and thus contribute to the specificity of PKA signalling. This local constriction of PKA is crucial for many of PKA‟s functions. The aim of this project was to gain mechanistic insight into the control of cardiac myocyte contractility and arginine-vasopressin (AVP)-mediated water reabsorption in renal principal cells by the analysis of the interactions of AKAPs with PKA and other proteins. A further aim was the identification of inhibitors of AKAP-PKA interactions for use as molecular tools and elucidation of the function of such interactions but also because chemical compounds modulating AKAP functions and altering compartmentalized cellular signalling may pave the way to new concepts for the treatment of diseases with a high medical need such as renal diseases and, in particular, heart failure. A major outcome of the project is the development of terpyridin-based α-helix mimetics for inhibition of AKAP- PKA interactions. These are the first in silico-designed non-peptidic agents for interference with such interactions. The use of our previously identified small molecule, FMP-API-1, which also inhibits AKAP-PKA interactions revealed a negative feedback mechanisms controlling cAMP synthesis in cardiac myocytes. We identified new AKAP18δ interactions and characterised their role in the control of cardiac myocytes contractility; with vacuolar H+-ATPase we identified a protein that controls local PKA signalling in renal principal cells and thereby AVP-mediated water reabsorption, presumably because it functions as an AKAP. We identified GSK3β interacting protein as an AKAP integrating PKA and GSK3β signalling.
Publications
- (2010) Glycogen synthase kinase 3β interaction protein functions as an A-kinase anchoring protein. The Journal of Biological Chemistry 285: 5507-5521
Hundsrucker C, Skroblin P, Christian F, Zenn HM, Popara V, Joshi M, Eichhorst J, Wiesner B, Herberg FW, Reif B, Rosenthal W, Klussmann E
(See online at https://doi.org/10.1074/jbc.M109.047944) - (2010) Mechanisms of protein kinase a anchoring. International Review of Cell and Molecular Biology 283: 235-330
Skroblin P, Grossmann S, Schafer G, Rosenthal W, Klussmann E
(See online at https://doi.org/10.1016/S1937-6448(10)83005-9) - (2011) Small molecule AKAP-protein kinase A (PKA) interaction disruptors that activate PKA interfere with compartmentalized cAMP signaling in cardiac myocytes. The Journal of Biological Chemistry 286: 9079-9096
Christian F, Szaszak M, Friedl S, Drewianka S, Lorenz D, Goncalves A, Furkert J, Vargas C, Schmieder P, Gotz F, Zuhlke K, Moutty M, Gottert H, Joshi M, Reif B, Haase H, Morano I, Grossmann S, Klukovits A, Verli J, Gaspar R, Noack C, Bergmann M, Kass R, Hampel K, Kashin D, Genieser HG, Herberg FW, Willoughby D, Cooper DM, Baillie GS, Houslay MD, von Kries JP, Zimmermann B, Rosenthal W, Klussmann E
(See online at https://doi.org/10.1074/jbc.M110.160614) - (2012) A-kinase anchoring proteins as potential drug targets. British Journal of Pharmacology 166: 420-433
Tröger J, Moutty MC, Skroblin P, Klussmann E
(See online at https://doi.org/10.1111/j.1476-5381.2011.01796.x) - (2012) Mechanism for targeting the A-kinase anchoring protein AKAP18δ to the membrane. The Journal of Biological Chemistry 287: 42495-42501
Horner A, Goetz F, Tampe R, Klussmann E, Pohl P
(See online at https://doi.org/10.1074/jbc.M112.414946) - (2013) Highly Functionalized Terpyridines as Competitive Inhibitors of AKAP-PKA Interactions. Angew Chem Int Ed Engl 52:12187-12191
Schäfer G, Milic J, Eldahshan A, Gotz F, Zuhlke K, Schillinger C, Kreuchwig A, Elkins JM, Abdul Azeez KR, Oder A, Moutty MC, Masada N, Beerbaum M, Schlegel B, Niquet S, Schmieder P, Krause G, von Kries JP, Cooper DM, Knapp S, Rademann J, Rosenthal W, Klussmann E
(See online at https://doi.org/10.1002/anie.201304686) - (2013) Small- Molecule Screening Identifies Modulators of Aquaporin-2 Trafficking. Journal of the American Society of Nephrology 24:744-58
Bogum J, Faust D, Zuhlke K, Eichhorst J, Moutty MC, Furkert J, Eldahshan A, Neuenschwander M, von Kries JP, Wiesner B, Trimpert C, Deen PM, Valenti G, Rosenthal W, Klussmann E
(See online at https://doi.org/10.1681/ASN.2012030295)
