Modulation of the cardiac sodium channel Nav1.5 by fibroblast growth factor homologous factor 1B.
We have previously shown that fibroblast growth factor homologous factor 1B (FHF1B), a cytosolic member of the fibroblast growth factor family, associates with the sensory neuron-specific channel Na(v)1.9 but not with the other sodium channels present in adult rat dorsal root ganglia neurons. We show in this study that FHF1B binds to the C terminus of the cardiac voltage-gated sodium channel Na(v)1.5 and modulates the properties of the channel. The N-terminal 41 amino acid residues of FHF1B are essential for binding to Na(v)1.5, and the conserved acidic rich domain (amino acids 1773-1832) in the C terminus of Na(v)1.5 is sufficient for association with this factor. Binding of the growth factor to recombinant wild type human Na(v)1.5 in human embryonic kidney 293 cells produces a significant hyperpolarizing shift in the voltage dependence of channel inactivation. An aspartic acid to glycine substitution at position 1790 of the channel, which underlies one of the LQT-3 phenotypes of cardiac arrythmias, abolishes the interaction of the Na(v)1.5 channel with FHF1B. This is the first report showing that interaction with a growth factor can modulate properties of a voltage-gated sodium channel.
Liu
Chuan-ju
CJ
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Dib-Hajj
Sulayman D
SD
Renganathan
Muthukrishnan
M
Cummins
Theodore R
TR
Waxman
Stephen G
SG
D000595:Amino Acid Sequence; D017124:Conserved Sequence; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000737:chemistry / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides / Q000502:physiology; D017354:Point Mutation; D015222:Sodium Channels / Q000737:chemistry / Q000502:physiology*; D014162:Transfection
C486356:FGF12 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C491886:SCN11A protein, human; C568320:SCN5A protein, human; C491885:Scn11a protein, mouse; C568321:Scn5a protein, mouse; C568322:Scn5a protein, rat; D015222:Sodium Channels; D005346:Fibroblast Growth Factors