In 1890 Wilhelm Ostwald (Nobel Prize in Chemistry 1909) proposed that the electrical signals measured in living tissue could be caused by ions moving in and out through cell membranes. This electro-chemical idea rapidly achieved acceptance. The notion of the existence of some type of narrow ion channel arose in the 1920s. The two British scientists Alan Hodgkin and Andrew Huxley made a major breakthrough at the beginning of the 1950s and for this were awarded the Nobel Prize in Physiology or Medicine in 1963. They showed how ion transport through nerve cell membranes produces a signal that is conveyed from nerve cell to nerve cell like a relay race baton. It is primarily sodium and potassium ions, Na+ and K+, that are active in these reactions.
Thus as much as fifty years ago there was well-developed knowledge of the central functions of the ion channels. They had to be able to admit one ion type selectively, but not another. Likewise, it had to be possible for the channels to open and shut and sometimes to conduct ions in one direction only. But how this molecular machinery really worked remained a mystery.
During the 1970s it was shown that the ion channels were able to admit only certain ions because they were equipped with some kind of ”ion filter”. Of particular interest was the finding of channels that admit potassium ions but not sodium ions – even though the sodium ion is smaller than the potassium ion. It was suspected that oxygen atoms in the transport protein played an important role as “substitutes” for the water molecules with which the potassium ion surrounds itself in a solution of water and from which it must free itself during entry to the channel. Only the Ion can pass, not it hydrated counterpart.
Physically being able to measure this hypothesis was difficult – what was now needed was high-resolution pictures of the kind that only X-ray crystallography can provide. The problem was that it is extremely difficult to determine the structure of membrane proteins with this method, and the ion channels were no exception. Membrane proteins from plants and animals are more complicated and difficult to work with than those from bacteria. Using bacterial channel proteins that resemble human ion channels as closely as possible might perhaps could simplify things.
Roderick MacKinnon, M.D. (Tufts Medical School, 1982 - Professor of Molecular Neurobiology and Biophysics at The Rockefeller University in New York, USA- 2003 Nobel Prize in Chemistry) began a to do research in the field of ion channels. Realizing higher-resolution structures were needed for understanding how ion channels function, he learned the fundamentals of X-ray crystallography. In April 1998 he proposed a structure of an ion channel.
First ion channel mapped – atom by atom (MacKinnon, 1998)
In 1998 MacKinnon determined the first high-resolution structure of an ion channel, called KcsA, from the bacterium Streptomyces lividans. MacKinnon revealed for the first time how an ion channel functions at atomic level... it uses an ion filter, which admits potassium ions and stops sodium ions. His ability with X-ray crystallography made it possible to unravel how the ions passed through the channel. The ions could also be visualized in the crystal structure – surrounded by water molecules just before they enter the ion filter; right in the filter, and when they meet the water on the other side of the filter (fig. 1).
Fig 1. The ion channel permits passage of potassium ions but not sodium ions. The oxygen atoms of the ion filter form an environment very similar to the water environment outside the filter. The cell may also control opening and closing of the channel.
MacKinnon could explain how the potassium ions but not sodium ions were admitted through the filter... namely, because the distance between the potassium ion and the oxygen atoms of the amino acids of in the filter region is the same as that between the potassium ion and the oxygen atoms in the water molecules surrounding the potassium ion when it is hydrated in aqueous solution outside the filter. Thus it can slide through the filter unopposed. However, the sodium ion, which is smaller than the potassium ion, can not pass through the channel. This is because it does not fit between the oxygen atoms in the filter and therefore remains in the water solution. The ability of the channel to strip the potassium ion of its water and allow it to pass at no cost in energy is a kind of selective catalyzed ion transport.
OUTSIDE THE ION FILTER (upper fig.)
Outside the cell membrane the ions are bound to water molecules with certain distances to the oxygen atoms of the water.
INSIDE THE ION
FILTER (lower fig.)
The sodium ions, which are smaller, do not fit in between the oxygen atoms in the filter. This prevents them from entering the channel.
Cells must also be able to control the opening and closing of ion channels. MacKinnon has shown that this is achieved by a gate at the bottom of the channel which opened and closed a molecular “sensor”. This sensor is situated close to the gate. Certain sensors react to certain signals, e.g. an increase in the concentration of calcium ions [Ligand Gated Channel], an electric voltage over the cell membrane, [Voltage Gated Channel], or binding of a signal molecule of some kind [Stress Activated Gated Channel]. By evolving different molecular sensors to ion channels, nature has created ion channels that respond to a large number of different environmental signals.
Ion Channels & Diseases
Membrane channels seem to be a precondition for all living matter. For this reason, increased understanding of their function constitutes an important basis for understanding many disease states. Dehydration of various types, and sensitivity to heat, are connected with the efficacy of the aquaporin ion channels. The European heat waves of recent years, for example, resulted in many deaths where the cause has sometimes been connected to problems in maintaining the body-fluid balance. In these processes the aquaporins are of crucial importance.
Disturbances in ion channel function can lead to serious diseases of the nervous system as well as the muscles, e.g. the heart. This makes the ion channels important drug targets for the pharmaceutical industry.
"The structure of the potassium channel: Molecular basis of K+ conduction and selectivity". D.A. Doyle, J. Morais Cabral, R.A. Pfuetzner, A. Quo, J.M. Gulbis, S.L. Cohen, B.T. Chait and R. MacKinnon. Science 280 (1998) 69-77.
"Energetic optimization of ion conduction rate by the K+ selectivity filter". J.H. Morais-Cabral, Y. Zhou and R. MacKinnon. Nature 414 (2001) 37-47.
"Crystal structure and mechanism of a calcium-gated potassium channel", Jiang, Y., Lee, A., Chen, J., Cadene, M., Chait, B.T., and MacKinnon, R. (2002). Nature 417, 515-522.
1998 HHMI Press release -
Announcing Structure of the K-Channel. (Mackinnon website)
U of Illinois -
Beckman Institute for
Advanced Science and Technology
Theoretical and Computational Biophysics Group
ion channel webpages - http://www.ks.uiuc.edu/Research/smd_imd/kcsa/