A carboxyl-terminal hydrophobic interface is critical to sodium channel function. Relevance to inherited disorders.
Perturbation of sodium channel inactivation, a finely tuned process that critically regulates the flow of sodium ions into excitable cells, is a common functional consequence of inherited mutations associated with epilepsy, skeletal muscle disease, autism, and cardiac arrhythmias. Understanding the structural basis of inactivation is key to understanding these disorders. Here we identify a novel role for a structural motif in the COOH terminus of the heart NaV1.5 sodium channel in determining channel inactivation. Structural modeling predicts an interhelical hydrophobic interface between paired EF hands in the proximal region of the NaV1.5 COOH terminus. The predicted interface is conserved among almost all EF hand-containing proteins and is the locus of a number of disease-associated mutations. Using the structural model as a guide, we provide biochemical and biophysical evidence that the structural integrity of this interface is necessary for proper Na+ channel inactivation gating. We thus demonstrate a novel role of the sodium channel COOH terminus structure in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it.
Glaaser
Ian W
IW
Department of Pharmacology, Columbia University, New York, New York 10032, USA.
Bankston
John R
JR
Liu
Huajun
H
Tateyama
Michihiro
M
Kass
Robert S
RS
D020106:Acrylamide / Q000737:chemistry; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000151:congenital / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D019295:Computational Biology / Q000379:methods; D020832:EF Hand Motifs; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015640:Ion Channel Gating / Q000235:genetics; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D015222:Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics; D014364:Tryptophan / Q000737:chemistry
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010446:Peptide Fragments; D021122:Protein Subunits; C568320:SCN5A protein, human; D015222:Sodium Channels; D020106:Acrylamide; D014364:Tryptophan