Fibroblast Growth Factor Homologous Factor 13 Regulates Na+ Channels and Conduction Velocity in Murine Hearts

• Published in: Circulation research 2011-09, Vol.109 (7), p.775-782
• Main Authors: Wang, Chuan, Hennessey, Jessica A, Kirkton, Robert D, Wang, Chaojian, Graham, Victoria, Puranam, Ram S, Rosenberg, Paul B, Bursac, Nenad, Pitt, Geoffrey S
• Format: Article
• Language: English
• Subjects: Action Potentials; Animals; Animals, Newborn; Biological and medical sciences; Biotinylation; Cells, Cultured; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Fundamental and applied biological sciences. Psychology; Heart Ventricles - metabolism; Ion Channel Gating; Kinetics; Mice; Mice, Inbred C57BL; Mutation; Myocytes, Cardiac - metabolism; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Protein Binding; Rats; Rats, Sprague-Dawley; RNA Interference; RNA, Messenger - metabolism; Sarcolemma - metabolism; Sodium - metabolism; Sodium Channels - genetics; Sodium Channels - metabolism; Transfection; Vertebrates: cardiovascular system; Voltage-Sensitive Dye Imaging
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.111.247957

RATIONALE:Fibroblast growth factor homologous factors (FHFs), a subfamily of fibroblast growth factors (FGFs) that are incapable of functioning as growth factors, are intracellular modulators of Na channels and have been linked to neurodegenerative diseases. Although certain FHFs have been found in embryonic heart, they have not been reported in adult heart, and they have not been shown to regulate endogenous cardiac Na channels or to participate in cardiac pathophysiology. OBJECTIVE:We tested whether FHFs regulate Na channels in murine heart. METHODS AND RESULTS:We demonstrated that isoforms of FGF13 are the predominant FHFs in adult mouse ventricular myocytes. FGF13 binds directly to, and colocalizes with, the NaV1.5 Na channel in the sarcolemma of adult mouse ventricular myocytes. Knockdown of FGF13 in adult mouse ventricular myocytes revealed a loss of function of NaV1.5-reduced Na current density, decreased Na channel availability, and slowed NaV1.5-reduced Na current recovery from inactivation. Cell surface biotinylation experiments showed ≈45% reduction in NaV1.5 protein at the sarcolemma after FGF13 knockdown, whereas no changes in whole-cell NaV1.5 protein or in mRNA level were observed. Optical imaging in neonatal rat ventricular myocyte monolayers demonstrated slowed conduction velocity and a reduced maximum capture rate after FGF13 knockdown. CONCLUSION:These findings show that FHFs are potent regulators of Na channels in adult ventricular myocytes and suggest that loss-of-function mutations in FHFs may underlie a similar set of cardiac arrhythmias and cardiomyopathies that result from NaV1.5 loss-of-function mutations.