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Pharmacological Approaches for Delineating Functions of AKAP-Based Signalling Complexes and Finding Therapeutic Targets

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Microdomains in the Cardiovascular System

Part of the book series: Cardiac and Vascular Biology ((Abbreviated title: Card. vasc. biol.,volume 3))

Abstract

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.

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Abbreviations

AC:

Adenylyl cyclase

AKAP:

A-kinase anchoring protein

AKB:

A-kinase-binding domain

D/D domain:

Docking/dimerisation domain of PKA

Epac:

Exchange proteins directly activated by cAMP

PDE:

Phosphodiesterase

PKA:

cAMP-dependent protein kinase A

STAD:

Stapled anchoring disruptor

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Acknowledgements

This work was supported by grants from the Else Kröner-Fresenius-Stiftung (2013_A145), the German-Israeli Foundation (G.I.F. I-1210-286.13/2012), the German Centre for Cardiovascular Research (DZHK 81X210012) and the Deutsche Forschungsgemeinschaft (DFG KL1415/7-1) to E. K.

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  1. Max Delbrueck Center for Molecular Medicine Berlin (MDC) in the Helmholtz Association, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Katharina Schrade & Enno Klussmann

  2. DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Oudenarder Strasse 16, 13347, Berlin, Germany

    Enno Klussmann

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  1. Institute of Experimental Cardiovascular Research, University Medical Center, Hamburg-Eppendorf, Germany

    Viacheslav Nikolaev

  2. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Manuela Zaccolo

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Schrade, K., Klussmann, E. (2017). Pharmacological Approaches for Delineating Functions of AKAP-Based Signalling Complexes and Finding Therapeutic Targets. In: Nikolaev, V., Zaccolo, M. (eds) Microdomains in the Cardiovascular System. Cardiac and Vascular Biology, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-54579-0_4

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