The β–adrenergic control of electro-energetic coupling in human induced pluripotent stem cell-derived cardiac cells

• Applicant: Professor Dr. Guiscard Seebohm
• Subject Area: Anatomy and Physiology ; Biochemistry ; Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567500531

The human cardiac myocyte adapts to acute stress and increased performance during exercise in response to β–adrenergic control. Targets to β–adrenergic signalling are the antagonistic L-type Ca2+ channels and KCNQ1/KCNE1 K+ channels. Congenital mutations in KCNQ1/KCNE1 channels cause Long QT syndromes 1 and 5 (LQTS 1/5) with elongated QT intervals in the electrocardiogram that are associated with aberrant β–adrenergic response observable as atypical prolongation of the QT interval and QT hysteresis under exercise and catecholamine infusion. However, the molecular mechanism(s) underlying this inverse β–adrenergic response in cardiomyocytes (CM) have remained enigmatic and will be studied in this project. We hypothetise that KCNQ1 integrates β–adrenergic stimuli into adjusted reaction of both, situation adapted action potential and metabolic state in CM. The aim of this project is to elucidate the molecular mechanisms underlying the coordinated KCNQ1/KCNE1 K+ channel function at the plasma membrane and potential KCNQ1/KCNE1 K+ channel functions in mitochondria (Mito). As an experimental basis we will utilize a KCNQ1-knockout / inducible KCNQ1-knockin channel hiPSC line which mimic LQTS1 in non-induced hiPSC CMs (loss of function) whereas KCNQ1/KCNE1 K+ channel induced/expressing CMs represent wild type (wt) conditions. As a second LQTS1 model, we will generate and express a LQT1-mutant hKCNQ1-G589D that disrupts PKA targeting to the channel. We plan to apply super resolution microscopy (SRM) and organell-isolation techniques to study the subcellular location of KCNQ1/KCNE1 channels in intact human hiPSC-derived ventricular-like CMs. Further, electrophysiological and metabolomics will be applied to study β–adrenergic physiological response of CM in control and LQT1 simulated conditions. We trust that this multidisciplinary approach will provide new insights into the molecular and cellular relevance of KCNQ1/KCNE1 K+ channels, apart from the regular function of CMs under control of βAS. Thereby we will also shed new light on the molecular patho-mechanism(s) of LQTS1 in patients leading to highly relevant clinical implications.

• DFG Programme: Research Grants