IDENTIFICATION OF A NOVEL SINOATRIAL NODE ACTIVITY REGULATOR: THE PROTEOHORMONE FGF23

FGF23 is a proteohormone mainly produced by osteocytes and osteoblasts whose canonical effect is to regulate the mineral metabolism through the FRS2 α/MAPK pathway activation. This hormone exerts its function mostly in the kidneys where it binds the FGF Receptor (FGFR) complex, which is composed by the FGFR and the specific FGF23 co-receptor, α- Klotho. Although the heart is not considered a canonical FGF23 target, data from Takeshita and colleagues highlight the expression of α-Klotho in the Sino-Atrial Node (SAN), the natural pacemaker of the heart and, interestingly, α-Klotho KO mice display intrinsic bradycardia and easily perish for sinus arrest or sinus block as a consequence of restrain stress. This suggests that SAN cells, as well as tubular renal cells, might be a physiological FGF23 target. Real-time and immunofluorescence experiments reveal that mouse SAN cells express both membrane α-Klotho and FGFRs (mainly FGFR1), and patch-clamp experiments have shown that incubating the SAN with FGF23 for 48hrs increases the spontaneous AP frequency of these cells through an increase in the If current conductance without affecting channel voltage dependence. Similar patch clamp experiments carried out using the pan-FGFR inhibitor, PD173074, and SAN cells isolated from α-Klotho KO mice suggested that FGF23 effects are mediated by the activation of the FGFR1-α-Klotho complex which can ultimately increase f-channels synthesis or decrease channel degradation. Our data also suggest that ERK phosphorylation might be part of the pathway linking the receptor complex activation to If increase. The data obtained in the mouse model were further confirmed in hiPSC-derived spontaneously beating cardiomyocytes; indeed, patch-clamp experiments reveal that the incubation with FGF23 1ng/mL for 48hrs increases both the AP frequency and the If current density. Since we were able to observe the same results in the two different pacemaker models (mice SAN and hiPSC-derived spontaneously beating cardiomyocytes) we can speculate that our findings might be applicable also to a human SAN. In conclusion this study demonstrates for the first time that FGF23 can regulate SAN electrical activity and provides novel insights into the cardio-renal axis.