The Binding of Fibroblast Growth Factor 23 (FGF23) to FGF Receptor-αKlotho Complex Increases Sinoatrial Electrical Activity

Aim: This study aims to investigate whether the Fibroblast Growth Factor 23 (FGF23) modulates the electrical activity of sinoatrial (SAN) cells. The canonical function of FGF23 is to regulate body phosphorus and calcium homeostasis by activating the FGF1 receptors (FGFR1)/α-Klotho complex in the kidney and parathyroid glands. High levels of FGF23 can induce cardiac arrhythmias by affecting cardiomyocyte's function in an α-Klotho independent manner. Although SAN cells are not traditionally considered targets of FGF23, the presence of α-Klotho in pacemaker and not in ventricular cells has raised this possibility. Methods: The effect of FGF23 was evaluated by patch-clamp experiments on mouse SAN and on human-induced pluripotent stem cells-derived pacemaker-like cardiomyocytes (hiPSC-derived pCMs). Results: Our data reveal that mouse SAN cells express both membrane α-Klotho and FGF23 receptors (FGFR) and that 48 h tissue incubation with FGF23 (10 ng/mL) increases the spontaneous action potential (AP) frequency of these cells through an increase in the funny If current. Patch-clamp experiments carried out using the pan-FGFR inhibitor, PD173074, and SAN cells isolated from α-Klotho hypomorphic mice suggested that FGF23 effects are mediated by the activation of the FGFR-α-Klotho complex. FGFRs expression data and FGF23-induced electrical modification were further confirmed in hiPSC-derived pCMs. Indeed, 48 h incubation of these cells with FGF23 increases both the AP frequency, in a dose-dependent manner, and the If current. Conclusions: This study represents the first evidence that FGF23 directly regulates the SAN electrical activity.