From Ionic Currents to Molecular Mechanisms The Structure and Function of Voltage-Gated Sodium Channels

tetrodotoxin binding activity and a protein of ‫072ف‬ kDa (Agnew et al., 1980). Subsequent purification studies showed that the sodium channel from mammalian brain is a complex of ␣ al., 1982), the tetrodotoxin-binding component of the sodium channel purified from eel electroplax is a single Voltage-gated sodium channels are responsible for the protein of 270 kDa (Miller et al., 1983), and the sodium rising phase of the action potential in the membranes channel from skeletal muscle is a complex of ␣ and ␤1 of neurons and most electrically excitable cells. Explora-subunits (Barchi, 1983). Reconstitution of neurotoxin-tion of the molecular properties of voltage-gated ion activated ion flux through purified sodium channels of channels began twenty years ago this past January with known subunit composition from brain and skeletal report of the discovery of the sodium channel protein muscle revealed that they contain a functional pore (Tal-by neurotoxin labeling methods (Agnew et al. into planar bilayer membranes demonstrated voltage-the early biochemical studies of sodium channels, fo-dependent activation (Hartshorne et al., 1985; Furman cuses primarily on the emerging view of the molecular et al., 1986). Together, these studies showed that the mechanisms of sodium channel function and regulation, purified sodium channel protein contained the essential and gives a perspective for future research on the ex-elements for ion conduction and voltage-dependent panding family of sodium channel proteins. Discoveries gating and opened the way for more detailed molecular of sodium channel diseases, new sodium channel analysis of the channel protein. genes, new modes of modulation of sodium channel Primary Structure and Functional Expression function, and new forms of sodium channel protein– Using both oligonucleotides encoding short segments protein interactions greatly expand the possible roles of the electric eel electroplax sodium channel as well for sodium channels in neuronal function and regulation. as antibodies directed against the channel protein, Noda et al. (1984) isolated cDNAs encoding the entire polypep-The Sodium Channel Protein tide from expression libraries of electroplax mRNA. Their Discovery and Purification work gave the initial insight into the primary structure Sodium currents were first recorded by Hodgkin and of a voltage-gated ion channel. The deduced amino acid Huxley, who used voltage clamp techniques to demon-sequence revealed a large protein with four internally strate the three key features that have come to char-homologous domains, each containing multiple poten-acterize the sodium channel: (1) voltage-dependent tial ␣-helical transmembrane segments (Figure 1B). The activation, (2) rapid inactivation, and …