Sodium channels structure

Fig. 16.1 Sodium channel structure. Schematic representation of the sodium channel subunits, a, ySl and / 2. (A) The a-subunit consists of four homologous intracelIularly linked domains (I—IV) each consisting of six connected segments (1-6). The segment 4 of each of the domains acts as the voltage sensor, physically moving out in response to depolarization resulting in activation of the sodium channel. The channel is inactivated rapidly by the linker region between III and IV docking on to the acceptor site formed by the cytoplasmic ends of S5 and S6 of domain IV. The / -subunits have a common structure, with the / 1 non-covalently bound, and f 2 linked by disulfide bonds to the a-channel...

Voltage-gated Sodium Channels Structure and Function... 

LAs block nerve conduction when applied locally to nervous tissue by a voltage- and frequency-dependent inhibition of sodium currents (see Voltage-gated Sodium Channels Structure and Function1). Due to this mechanism, they preferentially block hyperexcitable cells and interfere comparatively less with normal physiological sensory and motor function. However, they are not selective for pain-relevant sodium channel subtypes so that they have a relatively high risk of adverse effects associated with the central nervous and cardiovascular systems when administered systemically. Known LAs are not active when administered orally. 

Comparative structural analysis of sodium channel genes has permitted the development of testable hypotheses concerning the neurotoxin recognition properties of the sodium channel protein. However, specific elements of the deduced structure have not yet been definitively correlated with the molecular recognition of sodium channel-directed neurotoxins by discrete binding domains. It is, thus, not possible at the present time to know which pharmacological properties are determined by the sodium channel protein per se and which are determined by interactions between it and crucial features of its membrane environment. Clearly, it will be necessary to analyze the effects of specific modifications of sodium channel structure in a defined membrane environment in order to address these and other questions relating to sodium channel function. 

Phyletic Differences in Sodium Channel Structure Have Functional Significance... 

Kellenberger S, Schild L (2002) Epithelial sodium channel/degenerin family of ion channels a variety of functions for a shared structure. Physiol Rev 82 735-767... 

The three-dimensional structure of the sodium channel (from electric eel) was determined at 19-A resolution using cryo-electron microscopy and single-particle image analysis. The sodium channel has a bell-shaped outer surface of 135 A in height, 100 A in side length at the square bottom, and 65 A in diameter of the spherical top. An interesting finding is that there are several inner cavities connected to outer orifices. 

Catterall WA (2000) From ionic currents to molecular mechanisms the structure and function of voltage-gated sodium channels. Neuron 26 13-25... 

Catterall WA, Goldin AL, Waxman SG (2005) International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol Rev 57 397-409. 

The number of different proteins in a membrane varies from less than a dozen in the sarcoplasmic reticulum to over 100 in the plasma membrane. Most membrane proteins can be separated from one another using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), a technique that has revolutionized their study. In the absence of SDS, few membrane proteins would remain soluble during electrophoresis. Proteins are the major functional molecules of membranes and consist of enzymes, pumps and channels, structural components, antigens (eg, for histocompatibility), and receptors for various molecules. Because every membrane possesses a different complement of proteins, there is no such thing as a typical membrane structure. The enzymatic properties of several different membranes are shown in Table 41-2. 

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

These include nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and iV-methyl-D-aspartate (NMDA) receptors. Some general features of the structure, function, and evolution of biologically active peptides isolated from Conus venom are presented. 

Barhanin et al. (26) chemically modified the side chains of several residues to correlate structure and function in As II. Their results established the importance of charged residues for the function of the toxin. They showed that Arg-13 is essential for binding to the sodium channels as well as for toxicity, while the aspartate, glutamate, and lysine residues in the N-terminal segment of the protein are... 

It should be noted that in forming this dimeric channel structure all the hydrogen bonds are parallel to the channel axis and that the inner surface is lined with the polar polypeptide groups. In addition the various lipophilic side chains coat the outer wall of the structure and are thus in contact with the lipid hydrocarbon chains. The resulting gramicidin A channel is a most efficient means of ion transport with approximately 107 sodium ions traversing the channel per second, under conditions of 1 M NaCl, 100 mV applied potential and a temperature of 25 °C 225). The detailed mechanism by which this can be achieved is under active study 226). 

Stiihmer, W., Conti, F., Suzuki, H. et al. Structural parts involved in activation and inactivation of the sodium channel. Nature 339,597-603,1989. 

In order for the battery to function, the lithium iodide must be able to transfer ions. Lil adopts the sodium chloride structure, and there are no open channels for ions to use. In fact, the cell operation is sustained by the Schottky defect population in the... 

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