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Structure and function of voltage-gated Na+ channels. A. A 2-dimensional representation of the α (center), β1 (left), and β2 (right) subunits of the voltage-gated Na+ channel from mammalian brain. The polypeptide chains are represented by continuous lines with length approximately proportional to the actual length of each segment of the channel protein. Cylinders represent regions of transmembrane α helices. Ψ indicates sites of demonstrated N-linked glycosylation. Note the repeated structure of the 4 homologous domains (I through IV) of the α-subunit. Voltage sensing: The S4 transmembrane segments in each homologous domain of the α-subunit serve as voltage sensors. (+) Represents the positively charged amino acid residues at every third position within these segments. An electrical field (negative inside) exerts a force on these charged amino acid residues, pulling them toward the intracellular side of the membrane. Pore: The S5 and S6 transmembrane segments and the short membrane-associated loops between them (segments SS1 and SS2) form the walls of the pore in the center of an approximately symmetrical square array of the 4 homologous domains (see B). The amino acid residues indicated by circles in segment SS2 are critical for determining the conductance and ion selectivity of the Na+ channel and its ability to bind the extracellular pore blocking toxins tetrodotoxin and saxitoxin. Inactivation: The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate of the Na+ channel. It is thought to fold into the intracellular mouth of the pore and occlude it within a few milliseconds after the channel opens. Three hydrophobic residues (isoleucine–phenylalanine–methionine [IFM]) at the position marked H appear to serve as an inactivation particle, entering the intracellular mouth of the pore and binding to an inactivation gate receptor there. Modulation: The gating of the Na+ channel can be modulated by protein phosphorylation. Phosphorylation of the inactivation gate between homologous domains III and IV by protein kinase C slows inactivation. Phosphorylation of sites in the intracellular loop between homologous domains I and II by either protein kinase C or cyclic adenosine monophosphate (AMP)–dependent protein kinase reduces Na+ channel activation. B. The 4 homologous domains of the Na+ channel α-subunit are illustrated as a square array as viewed looking down on the membrane. The sequence of conformational changes that the Na+ channel undergoes during activation and inactivation is diagrammed. Upon depolarization, each of the 4 homologous domains undergoes a conformational change in sequence to an activated state. After all 4 domains have activated, the Na+ channel can open. Within a few milliseconds after opening, the inactivation gate between domains III and IV closes over the intracellular mouth of the channel and occludes it, preventing further ion conductance. [Reproduced with permission from Catterall W, Mackie K. Local Anesthetics. In: Hardman JG, Limbird LE, Gilman AF, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill; 2001:370.]
Source: Chapter 45. Pharmacology of Local Anesthetics*, Anesthesiology, 2e
Citation: Longnecker DE, Brown DL, Newman MF, Zapol WM. Anesthesiology, 2e; 2012 Available at: Accessed: October 30, 2017
Copyright © 2017 McGraw-Hill Education. All rights reserved