Small molecules for modulating the localisation of the water channel aquaporin-2—disease relevance and perspectives for targeting local cAMP signalling

  • Sandrine Baltzer
  • Enno KlussmannEmail author


The tight spatial and temporal organisation of cyclic adenosine monophosphate (cAMP) signalling plays a key role in arginine-vasopressin (AVP)-mediated water reabsorption in renal collecting duct principal cells and in a plethora of other processes such as in the control of cardiac myocyte contractility. This review critically discusses in vitro- and cell-based screening strategies for the identification of small molecules that interfere with AVP/cAMP signalling in renal principal cells; it features phenotypic screening and approaches for targeting protein–protein interactions of A-kinase anchoring proteins (AKAPs), which organise local cAMP signalling hubs. The discovery of novel chemical entities for the modulation of local cAMP will not only provide tools for elucidating molecular mechanisms underlying cAMP signalling. Novel chemical entities can also serve as starting points for the development of novel drugs for the treatment of human diseases. Examples illustrate how screening for small molecules can pave the way to novel approaches for the treatment of certain forms of diabetes insipidus, a disease caused by defects in AVP-mediated water reabsorption.


Aquaporin-2 AVP A-kinase anchoring protein AKAP cAMP signalling Protein kinase A PKA Screening Small molecule Protein–protein interaction PDE 


Author contribution statement

SB and EK analysed the data and wrote the manuscript. Both authors read and approved the manuscript.

Funding information

This work was supported by grants from the Bundesministerium für Bildung und Forschung (BMBF; 16GW0179K), the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG KL1415/7-1 and 394046635 – SFB 1365), the German Centre for Cardiovascular Research (DZHK) partner site Berlin (81X2100146) and the German Israeli Foundation (GIF, I-1452-203/13-2018).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Max Delbrück Center for Molecular Medicine Berlin (MDC), Helmholtz AssociationBerlinGermany
  2. 2.DZHK (German Centre for Cardiovascular Research), partner site BerlinBerlinGermany
  3. 3.Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Vegetative PhysiologyBerlinGermany

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