Scaffolding Proteins in Cardiac Myocytes

Contents

1 Stimulus-Specific or Localized cAMP-PKA Signaling in Cardiomyocytes 302

1.1 Compartmentalization of Individual Gs-Coupled GPCRs to Membrane Subdomains 303

1.2 The Role of PDZ-Domain-Containing Scaffolds 303

1.3 The Role of ß-Arrestin and AKAPs 306

2 Scaffolding Functions for the Cardiac Z-Disc 308

3 Scaffolds That Regulate PKC Signaling in Cardiomyocytes 309

4 Scaffolds That Influence Ion Channel Function 311

4.1 SCN5A (Voltage-Dependent Na+ Channel) 311

4.3 Ryanodine Receptor (RyR2) 314

4.4 KCNQ1 315

5. Scaffolds That Regulate Cardiac Hypertrophy 315

5.1 mAKAP-PKA-PDE4D3 Complexes 315

5.2 AKAP-Lbc and the Regulation of Rho and PKD 317

6 Conclusion 319

References 319

Abstract Post-translational modification, such as protein phosphorylation, plays a critical role to reversibly amplify and modulate signaling pathways. Since kinases and phosphatases have broad substrate recognition motifs, compartmentalization and localization of signaling complexes are required to achieve specific signals. Scaffolds are proteins that associate with two or more binding partners and function to enhance the efficiency and/or specificity of cellular signaling pathways. The identification of scaffolding proteins that control the tempo and/or spatial organization of signaling pathways in cells has benefited enormously from recent technological advances that allow for the detection of protein-protein interactions, including in vivo in intact cells. This review will focus on scaffolding proteins that nucleate multi-protein complexes (and could represent novel entry points into signaling pathways that might be amenable to therapeutic manipulation) in cardiomyocytes.

S.F. Steinberg

Departments of Pharmacology, College of Physicians and Surgeons, Columbia University,

630 West, 168 Street, New York, NY 10032, USA

[email protected]

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

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