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

Abstract

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.

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