TY - JOUR
T1 - Evolutionarily conserved intracellular gate of voltage-dependent sodium channels
AU - Oelstrom, Kevin
AU - Goldschen-Ohm, Marcel P.
AU - Holmgren, Miguel
AU - Chanda, Baron
N1 - Funding Information:
This project was supported by Research grants from NIH GM084140 and Shaw Scientist Award to B.C., the American Heart Association (Midwest Affiliate) Postdoctoral fellowship (12POST9440021) to M.P.G.-O. and Translational Cardiovascular predoctoral training grant (T32-HL07936) and Molecular and Cellular Pharmacology training grant (T32GM008668) to K.O. M.H. was supported by the intramural section of the National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke. We thank Dorothy Hanck (University of Chicago) and John Kyle (UW-Madison) for their generous gift of the sodium channel cysteine mutants S1578C-L1591C as well as San-dipan Chowdhury and Dr Brian Jarecki for useful discussions.
PY - 2014/3/12
Y1 - 2014/3/12
N2 - Members of the voltage-gated ion channel superfamily (VGIC) regulate ion flux and generate electrical signals in excitable cells by opening and closing pore gates. The location of the gate in voltage-gated sodium channels, a founding member of this superfamily, remains unresolved. Here we explore the chemical modification rates of introduced cysteines along the S6 helix of domain IV in an inactivation-removed background. We find that state-dependent accessibility is demarcated by an S6 hydrophobic residue; substituted cysteines above this site are not modified by charged thiol reagents when the channel is closed. These accessibilities are consistent with those inferred from open- and closed-state structures of prokaryotic sodium channels. Our findings suggest that an intracellular gate composed of a ring of hydrophobic residues is not only responsible for regulating access to the pore of sodium channels, but is also a conserved feature within canonical members of the VGIC superfamily.
AB - Members of the voltage-gated ion channel superfamily (VGIC) regulate ion flux and generate electrical signals in excitable cells by opening and closing pore gates. The location of the gate in voltage-gated sodium channels, a founding member of this superfamily, remains unresolved. Here we explore the chemical modification rates of introduced cysteines along the S6 helix of domain IV in an inactivation-removed background. We find that state-dependent accessibility is demarcated by an S6 hydrophobic residue; substituted cysteines above this site are not modified by charged thiol reagents when the channel is closed. These accessibilities are consistent with those inferred from open- and closed-state structures of prokaryotic sodium channels. Our findings suggest that an intracellular gate composed of a ring of hydrophobic residues is not only responsible for regulating access to the pore of sodium channels, but is also a conserved feature within canonical members of the VGIC superfamily.
UR - https://www.scopus.com/pages/publications/84896299188
U2 - 10.1038/ncomms4420
DO - 10.1038/ncomms4420
M3 - Article
C2 - 24619022
AN - SCOPUS:84896299188
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 3420
ER -