Sodium channels selectivity

From these observations, it became apparent that the frequency dependent capacitance must be due, at least partially, to gating particles, and, in particular, to those of sodium channels. If the capacitance change shown in Figure 6 is indeed due to sodium channels, then the change must be affected by TTX, which is known to block sodium channels selectively. Figure 7 shows the membrane capacitance at various potentials. As can be seen, TTX effectively eliminates the voltage dependence of... 

Electrophysiological studies (mainly using voltage-clamp and patch clamp) revealed the essential properties of the sodium channels kinetics of channel gating and selective ion permeation. Sodium channels are... 

The sodium channels are very selective for Na+ over K+, allowing Na+ influx down the electrochemical gradient to generate positive membrane potentials. The sodium channels are also permeable to Li+ and NH4+. The narrowest portion of the channel pore is estimated to be rectangular (3.1 x 5.2 A). 

This chapter briefly reviews the present understanding of the chemistry, origin, and distribution of the saxitoxins and methods for their detection. The second section of this chapter discusses studies on their pharmacology directed toward an understanding of the molecular basis for their strong, highly selective interaction with the sodium channel binding site. 

Over 40 different types of polypeptide toxins have been found in marine animals (i). Many of these toxins are exquisitely selective in their actions, affecting a single process or receptor at minute concentrations. So far the sea anemone and gastropod Conus) toxins have attracted the most attention as molecular probes of ion channels. In this chapter, we discuss several approaches which are being used to investigate, at the molecular level, the interactions of the sea anemone neurotoxic polypeptides with sodium channels. 

There appear to be at least two kinds of sodium channels, the common ones which are blocked by tetrodotoxin and alternate ones which are not affected by tetrodotoxin (57,58). It seems reasonable that species with a preponderance of this alternate type of sodium channel might evolve as the predominate form in response to the presence of tetrodotoxin. It is completely reasonable that in the presence of tetrodotoxin, species would be selected in which the nerve... 

It is suspected that these drugs selectively bind with the intracellular surface of sodium channels and block the entrance of sodinm ions into the cell. This leads to stoppage of the depolarization process, which is necessary for the diffusion of action potentials, elevation of the threshold of electric nerve stimulation, and thus the elimination of pain. Since the binding process of anesthetics to ion channels is reversible, the drug diffuses into the vascular system where it is metabolized, and nerve cell function is completely restored. 

To produce membrane depolarization, a current stimulus of sufficient intensity to exceed the outward K+ current must be appUed to the cell. If the depolarizing stimulus raises the membrane potential above a threshold value, sodium channels within the sarcolemmal membrane change their conformation and open their ion-selective pore, allowing Na to enter the cell driven by the electrochemical gradient. The open sodium channels raise the membrane potential toward the equilibrium potential of sodium (-f65 mV) and set into motion the intricate and precisely coordinated series of ion channel openings and closings leading to the characteristic action potential. 

Mechanism of Action A selective potassium channel blocker that prolongs repolar-ization without affecting conduction velocity by blocking one or more time-dependent potassium currents. Dofetilide has no effect on sodium channels or adrenergic alpha or beta receptors. Therapeutic Effect Terminates reentrant tachyarrhythmias,... 

An important aspect of antidepressant pharmacotherapy is selection based on the adverse effect profile of a specific medication, because most antidepressants are comparable in terms of efficacy. One of the major accomplishments of modern antidepressant development has been to improve the adverse effect profile of newer agents in comparison with TCAs and MAOIs without compromising efficacy (1). That has been accomplished by developing chemicals that retain the ability to affect sites of action that appear to be capable of mediating antidepressant efficacy (e.g., the serotonin uptake pump), but avoid effects on unnecessary sites of action (e.g., ACh receptor, fast sodium channels). This approach has led to both better tolerated and safer medications. Table 7-23 lists the common potential adverse affects of a number of antidepressants, as well as their relative severity. 

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