@article{9a49ed54190b4814a6d0377fd05e1631,
title = "Calcium-dependent regulation of the voltage-gated sodium channel hH1: Intrinsic and extrinsic sensors use a common molecular switch",
abstract = "The function of the human cardiac voltage-gated sodium channel Na V1.5 (hH1) is regulated in part by binding of calcium to an EF hand in the C-terminal cytoplasmic domain. hH1 is also regulated via an extrinsic calcium-sensing pathway mediated by calmodulin (CaM) via binding to an IQ motif immediately adjacent to the EF-hand domain. The intrinsic EF-hand domain is shown here to interact with the IQ motif, which controls calcium affinity. Remarkably, mutation of the IQ residues has only a minor effect on CaM affinity but drastically reduces calcium affinity of the EF-hand domain, whereas the Brugada mutation A1924T significantly reduces CaM affinity but has no effect on calcium affinity of the EF-hand domain. Moreover, the differences in the biochemical effects of the mutations directly correlate with contrasting effects on channel electrophysiology. A comprehensive model is proposed in which the hH1 IQ motif serves as a molecular switch, coupling the intrinsic and extrinsic calcium sensors.",
keywords = "Brugada, Calmodulin, EF hand, IQ motif, Long QT",
author = "Shah, {Vikas N.} and Wingo, {Tammy L.} and Weiss, {Kevin L.} and Williams, {Christina K.} and Balser, {Jeffrey R.} and Chazin, {Walter J.}",
year = "2006",
month = mar,
day = "7",
doi = "10.1073/pnas.0507397103",
language = "English",
volume = "103",
pages = "3592--3597",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "10",
}