EN
Role of AKAP18γ in the regulation of phospholamban function (RP4)
Principal Investigators
Project Summary and Goals
Regulation of cardiac contractility critically depends on cAMP/PKA signaling and its spatial confinement within subcellular microdomains. A central effector of this pathway is phospholamban (PLN), which controls SERCA2-mediated Ca²⁺ uptake into the sarcoplasmic reticulum (SR) and thereby governs relaxation of cardiomyocytes. While PLN regulation of SR function is well established, emerging evidence suggests that PLN also participates in endoplasmic reticulum (ER) Ca²⁺ homeostasis in human cardiomyocytes, with potential relevance for proteostasis and cardiac disease.
Recent studies indicate that PLN is organized within signaling microdomains scaffolded by A-kinase anchoring protein 18γ (AKAP18γ / AKAP7 long isoforms). However, despite biochemical and animal data, the functional role of AKAP18γ in compartmentalized PLN regulation in human cardiomyocytes remains poorly understood.
In this project, we will combine expertise in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), engineered heart tissues (EHTs), and cAMP signaling to test the hypothesis that AKAP18γ defines a critical microdomain that controls PLN/SERCA2 activity and thereby integrates SR and ER Ca²⁺ handling in human cardiomyocytes. We further hypothesise that disruption of this microdomain alters excitation–contraction coupling and intracellular Ca²⁺ compartmentation, with implications for cardiac contractile function and cellular homeostasis.
Aims Addressed by the Doctoral Candidates
- Investigate the role of AKAP18γ in regulating PLN/SERCA2 activity in human hiPSC-derived cardiomyocyte models.
- Define the functional impact of the PLN–AKAP18γ microdomain on SR and ER Ca²⁺
Publications
-
Altered endoplasmic reticulum calcium loading in human PLN-R14del cardiomyopathy. Borbein W, Dahmlos L, Saleem U, Reinsch M, Braren I, Schulze T, Klampe B, Cuello F, Stenzig J, Eschenhagen T, Hansen A (2025). Front Cell Dev Biol. 13:1627985. -
Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation. Cuello F, Knaust AE, Saleem U, Loos M, Raabe J, Mosqueira D, Laufer S, Schweizer M, van der Kraak P, Flenner F, Ulmer BM, Braren I, Yin X, Theofilatos K, Ruiz-Orera J, Patone G, Klampe B, Schulze T, Piasecki A, Pinto Y, Vink A, Hübner N, Harding S, Mayr M, Denning C, Eschenhagen T, Hansen A (2021). EMBO Mol Med. 13:e13074 -
Human Engineered Heart Tissue: Analysis of Contractile Force. Mannhardt I, Breckwoldt K, Letuffe-Brenière D, Schaaf S, Schulz H, Neuber C, Benzin A, Werner T, Eder A, Schulze T, Klampe B, Christ T, Hirt MN, Huebner N, Moretti A, Eschenhagen T, Hansen A (2016). Stem Cell Rep. 7:29-42. -
Optic atrophy 1 is an A-kinase anchoring protein on lipid droplets that mediates adrenergic control of lipolysis. Pidoux G, Witczak O, Jarnæss E, Myrvold L, Urlaub H, Stokka AJ, Küntziger T, Taskén K (2011). EMBO J. 30:4371-4386. -
Force and Calcium Transients Analysis in Human Engineered Heart Tissues Reveals Positive Force-Frequency Relation at Physiological Frequency. Saleem U, Mannhardt I, Braren I, Denning C, Eschenhagen T, Hansen A (2020). Stem Cell Rep. 14:312–324. -
Cell Banking of hiPSCs: A Practical Guide to Cryopreservation and Quality Control in Basic Research. Shibamiya A, Schulze E, Krauß D, Augustin C, Reinsch M, Schulze ML, Steuck S, Mearini G, Mannhardt I, Schulze T, Klampe B, Werner T, Saleem U, Knaust A, Laufer SD, Neuber C, Lemme M, Behrens CS, Loos M, Weinberger F, Fuchs S, Eschenhagen T, Hansen A, Ulmer BM (2020). Curr Protoc Stem Cell Biol. 55:e127