IGF-1 promotes cell surface expression of HCN4 pacemaker channels contributing to tachycardia

Insulin-like growth factor 1 (IGF-1) controls cardiac growth, metabolism, and contractility. Whereas IGF-1 deficiency is associated with cardiovascular risk, the activation of its signal transduction may be cardioprotective after acute myocardial infarction. Clinical studies evaluate the therapeutic potential of systemic IGF-1 in disease conditions including heart failure, and reported tachycardia as a common side effect. Here, we demonstrate that IGF-1 accelerates cardiac pacemaking in an ex vivo mouse sinoatrial node preparation read out by optical voltage mapping. Heterologous reconstitution experiments in Xenopus laevis oocytes combining extracellular epitope tagging and electrophysiology reveal an increase in cell surface expression of the main cardiac pacemaker channel isoform HCN4 by IGF-1, which stimulates the Rab11-dependent endosomal recycling of the channel protein. In summary, the study not only adds to the modes of HCN channel regulation by growth factor signaling, but may also extend our understanding of arrhythmogenesis, commonly observed in consequence of IGF-1 dysregulation including cardiac hypertrophy.