The ionic selectivity of voltagegated channels

Another essential feature is that every type of ion channel should be capable of a marked discrimination in favour of Na+, K+ or Ca2+ ions. Appropriate selectivity filters are invariably located in an extracellular pore region of the channel into which are tucked the four links between the outer ends of the S5 and S6 segments.

The first successful X-ray crystallographical study of any part of an ion channel has recently been carried out by Doyle et a/.(1998) on the structure of the potassium filter in bacterial K+ channels. This showed that the four S5—S6 links create an inverted cone cradling the narrow selectivity filter of the pore, 1.2nm in length, at its outer end. Here the main chain atoms create a stack of sequential carbonyl oxygen rings providing sites energetically suitable to be substituted for the hydration shell of a K+ ion. Above and below this narrow section of the K+ filter, the pore is somewhat wider so that the hydrated K+ ions are free to move on, while just two naked K+ ions can be fitted into the filter itself, although within it they cannot bypass one another. In every type of potassium channel, however it is gated, cDNA sequencing reveals the presence of an identically structured selectivity filter. The simple collision theory derived by Hodgkin & Keynes (1955^) to explain single-file diffusion of K+ ions in Sepia axons has therefore turned out to be precisely in line with the actual structure, and their crude mechanical model with ball bearings rattling about in two compartments connected by a narrow passage is remarkably close to a greatly scaled-up version of the filter designed by Nature perhaps a billion years ago.

In the case of the sodium channel, the selectivity filter is again located in the external pore, in the neighbourhood of the TTX binding site. From studies of the relative permeability of the sodium channel at the node of Ranvier to certain small organic cations, Hille has concluded that selection depends partly on a good fit between the dimensions of the penetrating ion and those of the mouth of the channel. As indicated in Fig. 5.5, only molecules measuring less than about 0.3 by 0.5 nm in cross-section are able to pass the filter. However, there were striking differences in permeability between some cations whose size was the same. Thus hydroxylamine (OH—NH+) and hydrazine (NH2—NH+) readily entered the channel, but methylamine (CH3-NH+) did not (Fig. 5.6). In order to explain the discrepancy, Hille proposed that the sodium channel is lined at its narrowest point with carbonyl oxygen atoms. Positively charged ions containing hydroxyl (OH) or amino (NH2) groups are able to pass through the channel by making hydrogen bonds with the oxygens, but those containing methyl (CH3) groups are excluded from it by their inability to form hydrogen bonds. The geometry of the situation is such that Na+ ions can divest themselves of all but one of their shell of water molecules by interacting with the strategically placed oxygen atoms, and the energy barrier that they encounter is therefore relatively low. The same is true for Li+, but the somewhat larger K+ ions cannot shed their hydration shell as easily, making PK for the sodium channel only one twelfth as great as PNa. However, only one Na+ ion at a time passes through the filter section, so

Direction of shake

Direction of shake

Direction of shake

Selectivity filter

Central cavity

Long vestibule

Fig. 5.5. Multi-ion single-file pores. (A) The mechanical model used by Hodgkin & Keynes (1955b) to mimic their K+ flux data from Sepia axons. Single-filing of the exchange of ball bearings between the two compartments took place only when they were connected by a pore long enough to contain three balls at a time, and too narrow for the balls to bypass one another. Reproduced with permission. (B) The free space in the pore of the potassium filter in bacterial potassium channels solved to 0.32 nm resolution by Doyle et al. (1998). Two fully dehydrated ions sit within the selectivity filter, while another partially hydrated ion occupies the central cavity and neighbouring vestibule. From McCleskey (1999). Reproduced from The Journal of General Physiology, 1999, vol. 113, p. 766, by copyright permission of The Rockefeller University Press.

Selectivity filter

Central cavity

Long vestibule

Fig. 5.5. Multi-ion single-file pores. (A) The mechanical model used by Hodgkin & Keynes (1955b) to mimic their K+ flux data from Sepia axons. Single-filing of the exchange of ball bearings between the two compartments took place only when they were connected by a pore long enough to contain three balls at a time, and too narrow for the balls to bypass one another. Reproduced with permission. (B) The free space in the pore of the potassium filter in bacterial potassium channels solved to 0.32 nm resolution by Doyle et al. (1998). Two fully dehydrated ions sit within the selectivity filter, while another partially hydrated ion occupies the central cavity and neighbouring vestibule. From McCleskey (1999). Reproduced from The Journal of General Physiology, 1999, vol. 113, p. 766, by copyright permission of The Rockefeller University Press.

Fig. 5.6. Scale drawings showing the effective sizes of lithium, sodium and potassium ions, each with one molecule of water, and of unhydrated hydroxylamine and hydrazine ions. The vertical lines 0.5 nm apart represent the postulated space between oxygen atoms available for cations able to pass through the sodium channel. Methylamine would look just like hydrazine in this kind of picture, but is nevertheless unable to enter the channel. After Hille (1971).

that Na+ channels do not display the single-file diffusion observed in K+ channels.

Calcium channels are normally permeable to strontium and barium ions, but completely impermeable to monovalent cations. When, however, external [Ca2+] is greatly reduced, the channels become permeable to both K+ and Na+ ions. It is therefore thought that the calcium channel has two high affinity Ca2+ binding sites at its mouth, and that if neither is occupied, monovalent ions can readily enter, while if one is occupied Na+ and K+ ions are effectively kept out by electrostatic repulsion. When both sites are occupied the flow both of divalent and monovalent cations rises again.

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