Direct AKAPMediated Protein Protein Interactions as Potential Drug Targets

Contents

1 A-Kinase-Anchoring Proteins Are Platforms for Cellular Signal Integration 484

2 Elucidation of AKAP Functions 485

2.1 Disruption of AKAP Function by Gene Targeting 486

2.2 Knockdown of AKAP Expression Using RNA. Approaches 487

2.3 Peptides as Disruptors of Protein-Protein Interactions 489

2.4 Peptides Interfering with Direct AKAP-Mediated Protein-Protein Interactions. . 489

2.5 Disruption of AKAP-PKA Interactions by Genetically Encoded Peptides 493

3 Direct AKAP-Mediated Protein-Protein Interactions in Compartmentalized cAMP Signalling as Potential Drug Targets 495

4 The Potential of Small Molecules for Pharmacological Interference with Direct AKAP-Mediated Protein-Protein Interaction 497

5 Summary and Conclusion 498

References 499

Abstract A-kinase-anchoring proteins (AKAPs) are a diverse family of about 50 scaffolding proteins. They are defined by the presence of a structurally conserved protein kinase A (PKA)-binding domain. AKAPs tether PKA and other signalling proteins such as further protein kinases, protein phosphatases and phosphodiesterases by direct protein-protein interactions to cellular compartments. Thus, AKAPs form the basis of signalling modules that integrate cellular signalling processes and limit these to defined sites. Disruption of AKAP functions by gene targeting, knockdown approaches and, in particular, pharmacological disruption of defined AKAP-dependent protein-protein interactions has revealed key roles of AKAPs in numerous processes, including the regulation of cardiac myocyte contractility and vasopressin-mediated water reabsorption in the kidney. Dysregulation

E. Klussmann

Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany Institut für Pharmakologie, Charité-Universitâtsmedizin, Freie Universität Berlin, Berlin, Germany [email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

of such processes causes diseases, including cardiovascular and renal disorders. In this review, we discuss AKAP functions elucidated by gene targeting and knockdown approaches, but mainly focus on studies utilizing peptides for disruption of direct AKAP-mediated protein-protein interactions. The latter studies point to direct AKAP-mediated protein-protein interactions as targets for novel drugs.

Abbreviations AKAP: A-kinase-anchoring protein; AVP: arginine-vasopressin; GEF: guanine nucleotide exchange factor; PKA: protein kinase A; SR: sarcoplasmic reticulum; PDE: phosphodiesterase; cAMP: cyclic adenosine monophosphate; PLN: phospholamban; RyR2: ryanodine receptors type 2; PP2B: protein phosphatase 2B/ calcineurin

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