Abstract 12913: Serotonin Regulates Qt-interval: Acceleration of Cardiac Repolarization by Enhanced Kv4.3 Membrane Trafficking

Abstract

Background: Elevated maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant of normal fetal development. However, what roles the elevated serotonin plays in the electrophysiology of the mother’s heart has not been studied. In the present study, we therefore assessed the relationship between QTc duration and serotonin and studied underlying mechanisms. Methods and results: During pregnancy, 5-HT and tryptophan hydroxylase 1, a rate-limiting enzyme of serotonin synthesis, were markedly increased in hearts and serum. We measured QT intervals and ventricular potassium outward currents in wild-type (WT) and 5-HT3a receptor knock-out ( Htr3a -/- ) mice at non-pregnant (NP) and late-pregnant (LP) state. The 5-HT as well as m-CPBG, an Htr3 agonist, increased I peak and I to,f densities with the shortening of QTc duration in WT NP, but not in WT LP and Htr3a -/- mice. Additionally an Htr3a antagonist, ondansetron (5 μM) decreased I peak and I to,f only in WT LP, but not in WT NP mice. In contrast, I peak and I to,f densities were unchanged upon 5-HT and m-CPBG application in left ventricular myocytes freshly-isolated from the Htr3a -/- -LP mice. Kv4.3 protein and Htr3a is co-localization in the membrane and t-tubule of cardiomyocytes. Co-immunoprecipitation showed that Kv4.3 protein directly interacts with 5-HT3a receptor. Moreover, the binding between 5-HT3a receptor and Kv4.3 was facilitated by 5-HT. This increase was mediated by 5-HT3a receptor dependent promotion of Kv4.3 channel trafficking to the cell membrane. However, these findings were not observed in WT LP mice. The heat-shock protein-90 (Hsp90) inhibitor geldanamycin abolished 5-HT-induced increase of I peak and I to,f densities. Finally, we evaluated and found that serotonin could shorten QTc interval by increasing potassium outward currents in rat and rabbit. Conclusion: Elevated 5-HT levels were associated shorter QTc intervals by acceleration of I peak and I to,f densities in mouse, rat and rabbit. 5-HT acts on Kv4.3 channels via enhanced 5-HT3a-receptor-medicated Hsp90 interaction, augments membrane trafficking and thereby increases repolarizing current. These results provide mechanistic insights into hormonal control of ventricular repolarization.