Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel.

Abstract

The principal voltage-sensitive sodium channel from human heart has been cloned, sequenced, and functionally expressed. The cDNA, designated hH1, encodes a 2016-amino acid protein that is homologous to other members of the sodium channel multigene family and bears >90% identity to the tetrodotoxin-insensitive sodium channel characteristic of rat heart and of immature and denervated rat skeletal muscle. Northern blot analysis demonstrates an =9.0-kilobase transcript expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. When expressed in Xenopus oocytes, hHl exhibits rapid activation and inactivation kinetics similar to native cardiac sodium channels. The single channel conductance of hHl to sodium ions is about twice that of the homologous rat channel and hHl is more resistant to block by tetrodotoxin (ICso = 5.7 pM). hHl is also resistant to Iu-conotoxin but sensitive to block by therapeutic concentrations of lidocaine in a use-dependent manner.

A critical residue for isoform difference in tetrodotoxin affinity is a molecular determinant of the external access path for local anesthetics in the cardiac sodium channel

“…The cardiac isoform appears to have a somewhat lower single-channel conductance (12,35,36), and this might alter the local Na ϩ concentration near the site where it affects the QX block, making the cardiac channel more sensitive to the QX block than the higher conductance 1 or nerve channels. This also seems unlikely because the rates of recovery from inside block, presumably by egress of drug to the outside, are also increased in the cardiac isoform and by the mutations allowing outside QX block.…”

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

“…The cardiac sodium current runs through the sodium channel Nav1.5 (formerly known as hH1) encoded by the gene SCN5A (Gellens et al, 1992). A small sustained component of the sodium current, the late sodium current (INa late ), is also active during phase 2 and phase 3 and contributes to determining the APD (Maltsev et al, 1998).…”

The genetic basis of Brugada syndrome: A mutation update

“…The genomic structure of SCN5A contains 28 exons spanning approximately 80 kb [Wang et al, 1996], and the gene has been mapped to chromosome 3p21 using fluorescence in situ hybridization [George et al, 1995]. The deduced 2,016 amino acid protein has a structure similar to that of other depolarizing sodium channels, that is, it contains four homologous domains, DI-DIV, each of which has six putative membrane-spanning regions, S1-S6 [Gellens et al, 1992] (see Fig. 2).…”

“…This gene encodes the a-subunit of the cardiac sodium channel conducting the depolarizing sodium inward current, I Na [Gellens et al, 1992]. The genomic structure of SCN5A contains 28 exons spanning approximately 80 kb [Wang et al, 1996], and the gene has been mapped to chromosome 3p21 using fluorescence in situ hybridization [George et al, 1995].…”