FIGURE 14-2 Structure and function of voltage-gated Na+ channels. A. A two-dimensional representation of the a (center), pj (left), and (32 (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 a helices. y indicates sites of demonstrated N-linked gly-cosylation. Note the repeated structure of the four homologous domains (I through IV) of the a subunit. Voltage Sensing. The S4 transmembrane segments in each homologous domain of the a subunit serve as voltage sensors. (+) represents the positively charged amino acid residues at every third position within these segments. Electrical field (negative inside) exerts a force on these charged amino acid residues, pulling them toward the intracellular side of the membrane; depolarization allows them to move outward. Pore. The S5 and S6 transmembrane segments and the short membrane-associated loop between them (P loop) form the walls of the pore in the center of an approximately symmetrical square array of the four homologous domains (see Panel B). The amino acid residues indicated by circles in the P loop 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 therein 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 ( p ) or cyclic AMP-dependent protein kinase (@) reduces Na+ channel activation. B.The four homologous domains of the Na+ channel a 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 four homologous domains sequentially undergoes a conformational change to an activated state. After all four 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.

244 SECTION III Drugs Acting on the Central Nervous System Table 14-1

Susceptibility to Block of Types of Nerve Fibers

Conduction Biophysical Classification

Anatomic Location

Diameter Myelin (mm)

Conduction Velocity

(m/sec) Function

Clinical Sensitivity to Block

A fibers

Was this article helpful?

0 0
Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook

Post a comment