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Chapter 16: Local Anesthetics

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For which one of the following sodium channel conformational states do local anesthetics have the MOST affinity?

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(A) rest

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(B) closed intermediate

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(C) open

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(D) inactivated

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The answer is C. According to the modulated receptor hypothesis, sodium channels respond to membrane depolarization by undergoing a series of conformational changes in their physical state (Figure 16-1). Each receptor is composed of an α-subunit and two β-subunits. The cycle begins at rest, with none of the four domains on the alpha-subunit activated. Once each of these change shape in sequence (closed intermediate stage), the sodium channel is activated (open stage), allowing sodium ions to enter the cell. Several milliseconds later, the channel becomes inactivated by yet another conformational change (inactivated stage), after which no further sodium ions can pass through.

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FIG. 16-1. 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 ...

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