Abstract 19538: KChIP2 Regulates the Cardiac Ca2+ Transient by Targeting Ryanodine Receptor Activity
Introduction: Cardiac ion channels and their respective interacting accessory subunits are critical in maintaining proper cardiac electrical activity. K+ channel interacting protein (KChIP2) was originally identified as an auxiliary subunit of Kv4 channels, contributing to the transient outward K+ current (Ito,f). However, recent studies have indicated that KChIP2 is a Ca2+ binding protein whose regulatory function is not restricted to Kv4 modulation. Indeed, the guinea pig myocardium does not express Kv4, yet still maintains expression of KChIP2, suggesting roles for KChIP2 beyond its canonical auxiliary interaction.
Methods and Results: Therefore, we tested the significance of guinea pig myocardial KChIP2 expression by acutely silencing its expression in isolated adult myocytes. As a consequence, we observed significant reductions in the Ca2+ transient amplitude and prolongation of the transient duration, as measured by Indo-1. This decrease in Ca2+ transient amplitude was also reinforced by a decrease in sarcomeric shortening. Notably, these results were observed in the presence of enhanced ICa,L and prolonged action potential duration, suggesting a disruption of fundamental Ca2+ handling proteins. Evaluation of SERCA2a, phospholamban, and ryanodine receptor identified no change in protein expression or phosphorylation status. Therefore, we evaluated functional changes in ryanodine receptor activity by measuring the characteristics of Ca2+ sparks in isolated cells. Reduced spark amplitude (-32.5% ± 3.15, p < .01), increased spark time-to-peak (43.1% ± 12.5, p < .01), and prolonged spark duration (19.1% ± 8.8, p < .05) followed the loss of KChIP2. These results suggest that the kinetics of RyR open probability are a target of KChIP2 loss.
Conclusions: Together, this highlights a novel association between KChIP2 expression and cardiac performance through Ca2+ transient regulation. Given that KChIP2 loss is repeatedly observed in the diseased heart, these novel observations suggest a critical role of KChIP2 in mediating declining cardiac performance.
Author Disclosures: D. Nassal: None. X. Wan: None. H. Liu: None. K.R. Laurita: None. I. Deschenes: None.
- © 2016 by American Heart Association, Inc.