Basic Properties of Voltage Gated Sodium Channels

Voltage-gated sodium channels are transmembrane proteins (Fig. 1A) that are responsible for the rapid depolarization

Closed Open Inactivated

Figure 1 Voltage-gated sodium channels form a pore in the cell membrane of neurons and muscle (A). These channels are gated by changes in the membrane potential (B). At negative potentials, voltage-gated sodium channels are typically "closed" (left). Depolarization produces a conformational change that "opens" the channel and allows ions to traverse the pore (center). At depolarized potentials, however, the ionic conductance is rapidly shut down by the action of an intracellular loop that "inactivates" the channel (right).

Closed Open Inactivated

Figure 1 Voltage-gated sodium channels form a pore in the cell membrane of neurons and muscle (A). These channels are gated by changes in the membrane potential (B). At negative potentials, voltage-gated sodium channels are typically "closed" (left). Depolarization produces a conformational change that "opens" the channel and allows ions to traverse the pore (center). At depolarized potentials, however, the ionic conductance is rapidly shut down by the action of an intracellular loop that "inactivates" the channel (right).

that underlies the upstroke of action potentials in neurons and are thus crucial to nerve impulse conduction. Because of their crucial role in electrogenesis, factors that decrease the activity of voltage-gated sodium channels can have major effects on axonal conduction. Indeed, several different clinically useful drugs that inhibit neuronal excitability, such as local anesthetics and anticonvulsants, act by suppressing the activity of voltage-gated sodium channels. To understand how blocking factors might alter the activity of voltage-gated sodium channels, it is useful to consider that sodium channels are found in one of three basic states or configurations (Fig. 1B). Typically, sodium channels are in a resting or "closed" state in neurons or muscle cells that are at rest (with a membrane potential of approximately -60 to -80 mV). Closed sodium channels do not conduct sodium ions, but are ready to be activated or "opened" when stimulated by membrane depolarization. In the open state, voltage-gated sodium channels form a pore in the cytoplasmic membrane that allows sodium ions to flow into the cell, depolarizing the cell and generating the upstroke of the action potential; however, most sodium channels rapidly transit into the "inactivated" state at depolarized potentials. In the inactivated state, the sodium channel pore is occluded by an inactivation particle from the intracellular side of the channel, thus blocking the flow of sodium ions and contributing to the termination of the action potential.

Several mechanisms by which drugs and other factors can reduce the activity of voltage-gated sodium channels have been identified. Some biological toxins, such as tetrodotoxin (the toxin found in the puffer fish Fugu), directly block sodium currents by binding in the pore of the channel and preventing the flow of sodium ions through the pore. Lidocaine and several other clinically relevant drugs primarily reduce sodium channel activity by enhancing the "inactivation" process of these channels (Fig. 2). This enhancement of sodium channel inactivation causes the channels to become inactivated at potentials where they would normally be in the closed or resting state, and can be measured by examining the voltage dependence of channel availability. The enhanced inactivation can also contribute to a use-dependent block, where channels that are rapidly and repeatedly activated are more susceptible to inactivation in the presence of the drug. Some of the blocking factors that may be important in inflammatory demyelinating diseases are thought to exert their effects via similar mechanisms. Blocking factors could affect axonal impulse transmission by directly blocking the sodium channel pore (like tetrodotoxin), by enhancing the inactivation process (like lidocaine), or by altering other gating properties of the sodium channels (perhaps preventing the closed-to-open gating transition).

Ten different voltage-gated sodium channel genes have been identified in humans (Nav1.1-Nav1.9 and Nax (Goldin et al., 2000)). Many of these different genes are known to

+ lidocaine

C Control

Figure 2 Voltage-gated sodium channels are inhibited by drugs such as lidocaine. (A) Lidocaine (500 pM) reduces the amplitude of the peak sodium current amplitude. (B) Lidocaine alters the voltage dependence of sodium channel steady-state inactivation and enhances inactivation. This is manifested as a reduction in the fraction of current available for activation at potentials near -80 mV after exposure to lidocaine (unfilled circles). (C) Lidocaine also induces use-dependent inhibition of sodium currents. Under control conditions (left) the peak sodium current amplitude is only slightly reduced during a 5-Hz train of stimulating depolarizations. By contrast, after exposure to lidocaine (right), the peak current amplitude substantially decreases during the same stimulation train.

Voltage (mV)

+ lidocaine produce voltage-gated sodium channels expressed in neurons; however, not all of these different channels are found in axons. Substantial evidence indicates that the specific iso-forms that are present differ between peripheral and central nervous system axons, developing and mature axons, myeli-nated and unmyelinated axons, normal and injured axons, and myelinated and demyelinated axons. For example, Nav1.6 is the predominant isoform located at nodes of Ranvier in adult axons but Nav1.2 is found in unmyelinated axons and axons undergoing myelination (Kaplan et al., 2001). In an animal model of inflammatory demyelination (Craner et al., 2003) and in human MS (Craner et al., 2004), Nav1.6 protein levels in optic nerve axons decrease and Nav1.2 protein levels increase, indicating that disease processes can alter sodium channel expression and distribution in axons. Altered sodium channel isoform expression could be important in determining the sensitivity of axons to specific blocking factors. For example, Sakurai and colleagues (1992) reported that intravenously administered lidocaine elicited reversible subclinical symptoms in 23 out of 28 patients with MS, but had no effect on 19 control subjects. Demyelinated fibers, with a relatively low density of sodium channels in the demyelinated internodal membrane regions, have low safety factors and thus may be sensitive to conduction block at dosages of lidocaine that do not alter conduction in normal fibers. Alternatively, Nav1.2 and Nav1.6 channels might have differences in their sensitivity to lidocaine that could contribute to the differential block. Regardless of the mechanism that underlies the apparent higher sensitivity of demyelinated fibers to lidocaine, this study clearly demonstrates that endogenous blocking factors, if they indeed do exist, could play important roles in negative symptoms associated with demyelinating disease.

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