Ion Selectivity

All ion channels conduct certain ions over others—a property referred to as ion selectivity. Some ion channels are permeable to a class of ions; cation channels are one example, though most ion channels conduct a single type of ion. The selectivity of some ion channels is extraordinary. Voltage-gated calcium channels are 1000 times more selective for Ca2+ over other cations and pass Ca2+ almost exclusively. This is remarkable considering that the concentrations of other ions such as Na + can be much higher than that of Ca2+. The mechanism by which ion channels pick and choose certain ions is still not fully understood.

At the molecular level, ions are little more than point charges with different valences. For ions with the same charge the only distinguishing feature is their ionic radius. Na + and K +, which both have a charge of + 1, have radii of 0.95 and 1.33 A, respectively. Another feature is the water molecules that surround and interact with the ion. In solution, ions are surrounded by multiple layers of water molecules that are continuously exchanging with other "free" waters around it. Based on the mobility of ions in solution, Na + behaves as though they are larger than K+. This is because its charge is concentrated in a smaller space and thus binds its waters of hydration more tightly.

The narrowest part of the pore has been termed by Bertil Hille as the ion selectivity filter. A filter with a fixed diameter is one way of explaining ion selectivity. In this view, ion channels are like sieves that allow small ions to pass but retain large ions. Although this mechanism is certainly at work in ion channels, an ion selectivity filter does not explain how an ion channel could be permeable only to large ions.

Figure 4 The "anatomy" of a typical ion channel. Ion channels are integral membrane proteins that sit in the plasma membrane. An ion is drawn sitting in a binding pocket in the ion selectivity filter (narrow part) as it passes through the ion channel. A gate (drawn as a door) swings open and closed.

scaffolding protein

Figure 4 The "anatomy" of a typical ion channel. Ion channels are integral membrane proteins that sit in the plasma membrane. An ion is drawn sitting in a binding pocket in the ion selectivity filter (narrow part) as it passes through the ion channel. A gate (drawn as a door) swings open and closed.

It is likely that the permeant ion makes direct contact with the ion channel at some points during its passage. These interactions at specific binding sites may explain how an ion channel can be selective for large ions or discriminate between ions of similar radii. The binding sites can be depicted with the aid of an "energy landscape'' diagram (Fig. 5a). Unfavorable locations are represented as regions of high energy, or peaks, whereas stable regions such as binding sites are represented by valleys. It is clear that some ion channels have more than one binding site within the channel. Multiple binding sites in close proximity may explain the high turnover rate of ion channels by setting up electrostatic repulsion between ions.

All potassium channel genes share a P region. The P region can be easily identified in potassium channel sequences since it contains the signature amino acid sequence GYG. The P region forms a part of the pore that is involved in ion selectivity since mutations in this region can alter the ion selectivity of potassium channels. The physical nature of the binding sites formed by the pore regions of most ion channels is unknown; however, it is likely that they are assembled from polar and charged amino acid sidechains or carbonyl oxygens from the protein backbone. These moieties could mimic the waters that may have been stripped away when the ion enters the pore. These interactions are likely to be transient and of low affinity given the high rate of turnover of an ion channel. One measure of the affinity can be obtained by measuring the current size at given ion concentrations (Fig. 5b). With no permeant ions present, an open ion channel will conduct zero current. As the concentration of ions is increased, the current will increase since the greater number of permeant ions will allow more ions to flow through the channel. Eventually, the current will reach a plateau or saturate. Plotted on a graph, the current can be fit with the Michaelis-Menton equation, and a constant (KM), a measure of the affinity of the ion channel for the ion,

Figure 5 Ion channels contain binding sites for ions in the pore. (a) Ions move through the pore in single file from left to right. Binding sites 1 and 2 are places where the ions make interactions with the ion channel. The procession through the pore can be represented on an energy landscape diagram in which the binding sites are drawn as valleys. (b) The current amplitude eventually plateaus as the concentration of permeant ions is increased. This data can be fit using the Michaelis-Menton equation to derive the Kd, a measure of affinity.

Figure 5 Ion channels contain binding sites for ions in the pore. (a) Ions move through the pore in single file from left to right. Binding sites 1 and 2 are places where the ions make interactions with the ion channel. The procession through the pore can be represented on an energy landscape diagram in which the binding sites are drawn as valleys. (b) The current amplitude eventually plateaus as the concentration of permeant ions is increased. This data can be fit using the Michaelis-Menton equation to derive the Kd, a measure of affinity.

can be obtained. Typically, ion channels show a Km in the millimolar range.

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