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Overview of the voltage-gated sodium channel family.

Yu FH, Catterall WA - Genome Biol. (2003)

Bottom Line: Selective permeation of sodium ions through voltage-dependent sodium channels is fundamental to the generation of action potentials in excitable cells such as neurons.These channels are large integral membrane proteins and are encoded by at least ten genes in mammals.The different sodium channels have remarkably similar functional properties, but small changes in sodium-channel function are biologically relevant, as underscored by mutations that cause several human diseases of hyperexcitability.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.

ABSTRACT
Selective permeation of sodium ions through voltage-dependent sodium channels is fundamental to the generation of action potentials in excitable cells such as neurons. These channels are large integral membrane proteins and are encoded by at least ten genes in mammals. The different sodium channels have remarkably similar functional properties, but small changes in sodium-channel function are biologically relevant, as underscored by mutations that cause several human diseases of hyperexcitability.

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A phylogenetic tree of voltage-gated sodium channel α-subunits. Rat sodium channel protein sequences were aligned using ClustalW and the tree was constructed using PAUP. The human chromosomes on which the human ortholog of each rat gene is found are shown on the right. Adapted from [13].
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Figure 3: A phylogenetic tree of voltage-gated sodium channel α-subunits. Rat sodium channel protein sequences were aligned using ClustalW and the tree was constructed using PAUP. The human chromosomes on which the human ortholog of each rat gene is found are shown on the right. Adapted from [13].

Mentions: Vertebrate α-subunit genes, especially those encoding the human and rodent sodium channels, are the best characterized to date. These sodium channels are greater than 50% identical in amino-acid sequence in the transmembrane and extracellular domains and are considered to be of one subfamily. According to the convention of the International Union of Pharmacologists, the nomenclature of sodium channels (for example, Nav1.1) consists of the chemical symbol of the principal permeating ion (Na) and the principal physiological regulator (voltage, subscript) followed by a number indicating the gene subfamily and a decimal that separates the number assigned to specific channel isoforms [13]. At least 20 exons encode each of the nine sodium channel α-subunit proteins. In an evolutionary analysis, the genes fall into four groups, and members of each group map to the same chromosome segment (Figure 3). The four chromosome segments containing sodium channel α-subunit genes are paralogous, and each also contains a cluster of Hox genes, which encode transcription factors involved in the control of developmental patterning [12]. Genes encoding sodium channels Nav1.1, Nav1.2, Nav1.3, and Nav1.7 are located on chromosome 2 in both human and mouse, and these channels share similarities in sequence, biophysical characteristics, the ability to be blocked by nanomolar concentrations of the neurotoxin tetrodotoxin, and broad expression in neurons [13]. A second cluster of genes encoding the channels Nav1.5, Nav1.8, and Nav1.9 is located on human chromosome 3p21-24 and to the orthologous region of chromosome 3 in mouse [13]. Although they are approximately 75% identical in amino-acid sequence to the group of channels on chromosome 2, these closely related sodium channels have amino-acid changes that confer varying degrees of tetrodotoxin resistance. In Nav1.5, the principal cardiac isoform, a single amino-acid change from phenylalanine to cysteine in the pore region of domain I is responsible for 200-fold reduction in tetrodotoxin sensitivity [14] relative to the channels encoded on chromosome 2. At the corresponding position in channels Nav1.8 and Nav1.9 the residue is serine, and this change results in even greater resistance to tetrodotoxin [15]. The latter two channels are preferentially expressed in peripheral sensory neurons [16,17]. The other two isoforms, Nav1.4 (which is expressed in skeletal muscle) and Nav1.6 (which is highly abundant in the central nervous system), have greater than 85% sequence identity and similar functional properties to the chromosome-2-encoded channels, including tetrodotoxin sensitivity in the nanomolar concentration range. Despite these similarities, phylogenetic analysis by parsimony suggests a more distant evolutionary relationship from the chromosome-2-encoded channels (Figure 3), consistent with their distinct chromosomal localizations - Nav1.4 on human chromosome 11 (mouse chromosome 17) and Nav1.6 on human chromosome 15 (mouse 12) [11,13].


Overview of the voltage-gated sodium channel family.

Yu FH, Catterall WA - Genome Biol. (2003)

A phylogenetic tree of voltage-gated sodium channel α-subunits. Rat sodium channel protein sequences were aligned using ClustalW and the tree was constructed using PAUP. The human chromosomes on which the human ortholog of each rat gene is found are shown on the right. Adapted from [13].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC153452&req=5

Figure 3: A phylogenetic tree of voltage-gated sodium channel α-subunits. Rat sodium channel protein sequences were aligned using ClustalW and the tree was constructed using PAUP. The human chromosomes on which the human ortholog of each rat gene is found are shown on the right. Adapted from [13].
Mentions: Vertebrate α-subunit genes, especially those encoding the human and rodent sodium channels, are the best characterized to date. These sodium channels are greater than 50% identical in amino-acid sequence in the transmembrane and extracellular domains and are considered to be of one subfamily. According to the convention of the International Union of Pharmacologists, the nomenclature of sodium channels (for example, Nav1.1) consists of the chemical symbol of the principal permeating ion (Na) and the principal physiological regulator (voltage, subscript) followed by a number indicating the gene subfamily and a decimal that separates the number assigned to specific channel isoforms [13]. At least 20 exons encode each of the nine sodium channel α-subunit proteins. In an evolutionary analysis, the genes fall into four groups, and members of each group map to the same chromosome segment (Figure 3). The four chromosome segments containing sodium channel α-subunit genes are paralogous, and each also contains a cluster of Hox genes, which encode transcription factors involved in the control of developmental patterning [12]. Genes encoding sodium channels Nav1.1, Nav1.2, Nav1.3, and Nav1.7 are located on chromosome 2 in both human and mouse, and these channels share similarities in sequence, biophysical characteristics, the ability to be blocked by nanomolar concentrations of the neurotoxin tetrodotoxin, and broad expression in neurons [13]. A second cluster of genes encoding the channels Nav1.5, Nav1.8, and Nav1.9 is located on human chromosome 3p21-24 and to the orthologous region of chromosome 3 in mouse [13]. Although they are approximately 75% identical in amino-acid sequence to the group of channels on chromosome 2, these closely related sodium channels have amino-acid changes that confer varying degrees of tetrodotoxin resistance. In Nav1.5, the principal cardiac isoform, a single amino-acid change from phenylalanine to cysteine in the pore region of domain I is responsible for 200-fold reduction in tetrodotoxin sensitivity [14] relative to the channels encoded on chromosome 2. At the corresponding position in channels Nav1.8 and Nav1.9 the residue is serine, and this change results in even greater resistance to tetrodotoxin [15]. The latter two channels are preferentially expressed in peripheral sensory neurons [16,17]. The other two isoforms, Nav1.4 (which is expressed in skeletal muscle) and Nav1.6 (which is highly abundant in the central nervous system), have greater than 85% sequence identity and similar functional properties to the chromosome-2-encoded channels, including tetrodotoxin sensitivity in the nanomolar concentration range. Despite these similarities, phylogenetic analysis by parsimony suggests a more distant evolutionary relationship from the chromosome-2-encoded channels (Figure 3), consistent with their distinct chromosomal localizations - Nav1.4 on human chromosome 11 (mouse chromosome 17) and Nav1.6 on human chromosome 15 (mouse 12) [11,13].

Bottom Line: Selective permeation of sodium ions through voltage-dependent sodium channels is fundamental to the generation of action potentials in excitable cells such as neurons.These channels are large integral membrane proteins and are encoded by at least ten genes in mammals.The different sodium channels have remarkably similar functional properties, but small changes in sodium-channel function are biologically relevant, as underscored by mutations that cause several human diseases of hyperexcitability.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.

ABSTRACT
Selective permeation of sodium ions through voltage-dependent sodium channels is fundamental to the generation of action potentials in excitable cells such as neurons. These channels are large integral membrane proteins and are encoded by at least ten genes in mammals. The different sodium channels have remarkably similar functional properties, but small changes in sodium-channel function are biologically relevant, as underscored by mutations that cause several human diseases of hyperexcitability.

Show MeSH
Related in: MedlinePlus