Overview of the voltage-gated sodium channel family

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.

Figure 1

Structure of voltage-gated sodium channels. (a) Schematic representation of the sodium-channel subunits. The α subunit of the Na_v1.2 channel is illustrated together with the β1 and β2 subunits; the extracellular domains of the β subunits are shown as immunoglobulin-like folds, which interact with the loops in the α subunits as shown. Roman numerals indicate the domains of the α subunit; segments 5 and 6 (shown in green) are the pore-lining segments and the S4 helices (yellow) make up the voltage sensors. Blue circles in the intracellular loops of domains III and IV indicate the inactivation gate IFM motif and its receptor (h, inactivation gate); P, phosphorylation sites (in red circles, sites for protein kinase A; in red diamonds, sites for protein kinase C); ψ, probable N-linked glycosylation site. The circles in the re-entrant loops in each domain represent the amino acids that form the ion selectivity filter (the outer rings have the sequence EEDD and inner rings DEKA). (b) The three-dimensional structure of the Na_v channel α-subunit at 20 Å resolution, compiled from electron micrograph reconstructions. Adapted from [6]. (c) Schematic representation of NaChBac, the bacterial voltage-gated sodium channel.

Figure 2

Mechanism of inactivation of sodium channels. (a) The hinged-lid mechanism. The intracellular loop connecting domains III and IV of the sodium channel is depicted as forming a hinged lid with the critical phenylalanine (F1489) within the IFM motif shown occluding the mouth of the pore during the inactivation process. The circles represent the transmembrane helices. (b) Three-dimensional structure of the central segment of the inactivation gate, as determined by multidimensional NMR. Side chains of the critical IFM motif residues (I1488, F1489 and M1490) are shown in yellow, and those of T1491, which is important for inactivation, and S1506, which is a protein-kinase-C-dependent phosphorylation site, are also indicated. Adapted from [4].

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].