Fibroblast Growth Factor Homologous Factor Modulation and Effect on Cardiac Ion Channel Trafficking

Duke University, Durham NC

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): Cardiac voltage-gated ion channels are a set of highly regulated proteins that control the rapid and efficient spread of cellular electrical activiy through the heart and enable the translation of electrical activity into mechanical contraction. Physiological function of ion channels requires dynamic trafficking to and from specific membrane compartments, regulated by ion channel modulators, and disorders of channel trafficking underlie various arrhythmia syndromes and heart failure. Here, I focus on uncovering the role of fibroblast growth factor homologous factors (FHFs), an emerging class of channel regulators that are loci for arrhythmogenic disorders, in the trafficking and function of both voltage-gated Na+ and Ca2+ channels. The proposed research will reveal mechanistic details of how FGF13, the predominant FHF in the rodent heart, controls Na+ and Ca2+ channel trafficking. Based on exciting preliminary data, I hypothesize that FGF13 acts as a brake for the reverse trafficking process and that loss-of-function mutations in FGF13 result in decreased amounts of functional Na+ and Ca2+ channels at the sarcolemma. The proposed studies exploit a new inducible and cardiac-specific Fgf13 knockout mouse model to define the specific roles of FGF13 and to determine if the regulatory mechanisms differ between Na+ and Ca2+ channels. Successful completion of this work will lead to a new understanding of FHFs in the heart and define how mutations in FHFs are associated with life-threatening arrhythmias.