Molecular struture of ion channels_1

B3 top view looking into the filter a k ion is in

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Unformatted text preview: d When the gate is closed, one K+ ion is located in the central cavity (Fig. 14). That K+ ion is surrounded by water molecules and is stabilized in the center because the lining of the central cavity is hydrophobic (water hating) and the four negatively charged ends of the helix that faces the cavity act as four, equidistant weak attractants that sort of hold the K+ molecule in its place (Fig. 13B3 and B4). There are two K+ ions in the selectivity filter, each separated by a water molecule, and oscillating between positions 13 and 24 of the filter. The K+ ion in the central cavity cannot enter the selectivity filter because of K+ in the selectivity filter repel it through electrostatic forces. K+ ions cannot move out of the filter because it is in the closed position. Thus, there is no flow of ions through the filter when the gate is closed. Figure 14. K+ ion channel in closed state. Note that the selectivity filter is pinched at the top thereby closing the filter to the extracellular fluids. One hydrated K+ ion is in the central cavity, stabilized by the four negative carbonyl charges from each of the four pore helices (only two pore helicies are shown). See text for further explanation. 14 Events when the gate is open Next, let us see what happens when the gate opens (Fig.15). Now the high intracellular concentration of K+ forces additional K+ into the central cavity. The repulsive force of the high K+ concentration in the cavity forces the K+ in the center of the cavity towards the selectivity filter. The negatively charged helices now strip the water molecules from the K+ ion allowing it to fit perfectly into site 4 of the filter (Fig. 15, panels 2 and 3). This is followed by a second K+ ion from the cavity into the filter. Each time a K+ is forced into the filter, it occupies one of the filter sites, and the full occupancy of the sites, with four dehydrated K+, changes the filter conformation to the open state. Now the electrostatic forces of the K+ ions in the filter force the K+ ion in site 4 out of the channel into the extracellular space (Fig. 15, panel 3). This vacant site is then filled by the K+ ion that was in site 3, which is turn is filled by the K+ ion that was in site 2, and so on. The K+ ion in site 1 is constantly replenished by the entering K+ ions that are repelled from the central cavity by the high K+ concentration in intracellular fluid that is "seen" or sensed in the central cavity (Fig. 15, panel 4). In this way, there is a "bucket brigade" type of movement of K+ ions through the selectivity filter into the extracellular space. When the gate closes, the central cavity no longer senses a high K+ concentration, and thus there is no longer a sufficient force on the lone K+ in the cavity to force it into the filter. As soon as the last K+ ion is forced from the filter into the extracellular space, leaving two K+ ions in the filter, the filter conformation changes, thereby closing the filter and preventing any of further flux of K+ ions out of the filter. In this condition, ionic current through the filter stops. Figure 15. K+ ion channel in the open state; both the activation gate (bottom) and the selectivity filter are open. Panels 14 show how the hydrated K+ in the central cavity is dehydrated and enters site 4 of the selectivity filter, thereby exerting electrostatic repulsive forces on the K+ ions in the sites above it, and forcing the K+ in site 1 into the extracellular space where it is then hydrated. This sequence is then repeated as a new K+ enters the filter. The K+ ions in each binding site in panel 1 are shaded so that each can be followed as each is successively driven upward and ultimately out of the filter into the extracellular space. 15 ! Why can't Na+ ions flow through the filter? The hallmark of the selectivity filter is that it passes only one type of ion, K+ in this case, and excludes all other ions. As described previously, the reason that K+ passes easily through the filter is because a dehydrated K+ fits precisely into a site, embraced by the negativity at each site, which mimics the embrace of the water molecules that surround the ion in solution (Fig.16). As far as the K+ ion is concerned, being hydrated or being in the filter are energetically equal, and thus the two states are in equilibrium. Thus as water is stripped from the K+ ion, it just slides into a binding site and can move through the binding site as readily as it diffuses in solution. But dehydrated Na+ ions are smaller than K+ ions, so why can't the smaller Na+ ions pass through the selectivity filter? The answer is that Na+ ions do not fit well in the sites of the selectivity filter that stabilize K+ ions, and thus the hydrated Na+ ion is far more stable than a dehydrated Na+ that entered the filter. The probability of the two states greatly favors hydration, as shown by the arrows in the right panel of Fig. 16. Let us explore this in a bit more detail. Imagine that the selectivity filer is open, and thus the external face of the selectivity filter is open to the extracellular fluid where there is a high concentration of Na+ that should drive Na+ into and through the filter. However, the dimensions of the segments fit K+ ions stripped of their surrounding water perfectly. Hydrated Na+ ions are too large to enter the pore. Dehydrated Na+ ions, although smaller than dehydrated K+ ions, fit poorly into the filter, and thus are far more likely to flip back to a hydrated state. The precise fit of K+ ions in the filter sites is the key feature that endows the K+ channel with its ion selectivity. H H H H H H Figure 16. Hydrated K+ and K+ ions are H H shown in the top panels. The dehydrated ions are shown in the bottom panel. Notice that the dehydrated K+ ion is larger than the dehydrated Na+ ion, but that the dehydrated Na+ ion fits poorly in the binding sites of the selectivity filter, while the K+ ion fits perfectly. H H H H H H H H 16...
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This note was uploaded on 09/17/2009 for the course BIO 365R taught by Professor Draper during the Spring '08 term at University of Texas.

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