Pharmacological approaches for delineating functions of AKAP- based signalling complexes and finding therapeutic targets

A-kinase anchoring proteins (AKAPs) comprise a family of scaffolding proteins that direct their interacting partners to defined cellular compartments. The interacting partners can comprise all proteins of canonical cAMP signalling: protein kinase A (PKA), PKA substrates, adenylyl cyclases, phosphodiesterases (PDEs) and protein phosphatases. AKAPs are central for compartmentalising these components and thus for achieving specificity of cAMP signalling cascades. Since AKAPs can additionally bind proteins of other signalling cascades, they constitute nodes for the integration of cellular signalling. Although general functions have been ascribed to several AKAPs, a detailed understanding of the roles of most of their individual protein-protein interactions is lacking. In particular, knowledge of the functions of individual AKAP-PKA interactions is scarce, as they are mediated by conserved domains and difficult to disrupt selectively. In this article, we will discuss pharmacological agents for interference with individual protein-protein interactions of AKAPs. We will mainly focus on recent progress in targeting AKAP-PKA interactions. Since AKAP-directed signalling is dysregulated in some diseases, such agents may be suitable for validating AKAPs as potential drug targets