Calcium-dependent regulation of the voltage-gated sodium channel hH1: intrinsic and extrinsic sensors use a common molecular switch.

Shah VN, Wingo TL, Weiss KL, Williams CK, Balser JR, Chazin WJ
Proc Natl Acad Sci U S A. 2006 103 (10): 3592-7

PMID: 16505387 · PMCID: PMC1450128 · DOI:10.1073/pnas.0507397103

The function of the human cardiac voltage-gated sodium channel Na(V)1.5 (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.

MeSH Terms (19)

Amino Acid Motifs Amino Acid Sequence Binding Sites Calcium Cell Line Humans In Vitro Techniques Kinetics Models, Biological Molecular Sequence Data Muscle Proteins Mutagenesis, Site-Directed Mutation Myocardium NAV1.5 Voltage-Gated Sodium Channel Peptide Fragments Recombinant Fusion Proteins Sequence Deletion Sodium Channels

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