Cargando…

KChIP2 regulates the cardiac Ca(2+) transient and myocyte contractility by targeting ryanodine receptor activity

Pathologic electrical remodeling and attenuated cardiac contractility are featured characteristics of heart failure. Coinciding with these remodeling events is a loss of the K(+) channel interacting protein, KChIP2. While, KChIP2 enhances the expression and stability of the Kv4 family of potassium c...

Descripción completa

Detalles Bibliográficos
Autores principales: Nassal, Drew M., Wan, Xiaoping, Liu, Haiyan, Laurita, Kenneth R., Deschênes, Isabelle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383259/
https://www.ncbi.nlm.nih.gov/pubmed/28384221
http://dx.doi.org/10.1371/journal.pone.0175221
Descripción
Sumario:Pathologic electrical remodeling and attenuated cardiac contractility are featured characteristics of heart failure. Coinciding with these remodeling events is a loss of the K(+) channel interacting protein, KChIP2. While, KChIP2 enhances the expression and stability of the Kv4 family of potassium channels, leading to a more pronounced transient outward K(+) current, I(to,f), the guinea pig myocardium is unique in that Kv4 expression is absent, while KChIP2 expression is preserved, suggesting alternative consequences to KChIP2 loss. Therefore, KChIP2 was acutely silenced in isolated guinea pig myocytes, which led to significant reductions in the Ca(2+) transient amplitude and prolongation of the transient duration. This change was reinforced by a decline in sarcomeric shortening. Notably, these results were unexpected when considering previous observations showing enhanced I(Ca,L) and prolonged action potential duration following KChIP2 loss, suggesting a disruption of fundamental Ca(2+) handling proteins. Evaluation of SERCA2a, phospholamban, RyR, and sodium calcium exchanger identified no change in protein expression. However, assessment of Ca(2+) spark activity showed reduced spark frequency and prolonged Ca(2+) decay following KChIP2 loss, suggesting an altered state of RyR activity. These changes were associated with a delocalization of the ryanodine receptor activator, presenilin, away from sarcomeric banding to more diffuse distribution, suggesting that RyR open probability are a target of KChIP2 loss mediated by a dissociation of presenilin. Typically, prolonged action potential duration and enhanced Ca(2+) entry would augment cardiac contractility, but here we see KChIP2 fundamentally disrupts Ca(2+) release events and compromises myocyte contraction. This novel role targeting presenilin localization and RyR activity reveals a significance for KChIP2 loss that reflects adverse remodeling observed in cardiac disease settings.