CFTR REVIEW PAGE
ION CHANNELS FOR BEGINNERS
The ABCs of Ion Channels
Part A How Ion Channels Work
Part B Things Ion Channels Do
Part C Types of Ion Channels Known "The Master List"
How Ion Channels Work
At some time in Earth's early history, perhaps when the planet was less than a billion years old, the ancestor of all present day living cells acquired a protective membrane in which to surround itself in. Made out of oily lipid, the advantages of this membrane barrier for the cell would have been considerable. Protection of the valuable interior contents of the cell from the harsh primordial environment probably was the major driving force. A membrane also provided this first cell with a higher concentration of needed metabolites and other "food" molecules by the simple act of confining them inside a small volume which is the cell's interior. However, cellular membranes create problems of their own for living systems, due to the same reason that made them so beneficial in the first place: they are very effective barriers to the transfer of large molecules as well as small negatively and positively charged molecules (ions) which are needed by the cell for various activities including growth and reproduction. As just about anyone who has ever tried to wash grease from their hands using water without soap knows, some types of chemicals, like oil and water, do not want to mix with each other. Such is the case for water-loving ions in the environment and the oily lipid membranes which guard the contents of all cells. The problem is that ions prefer to remain in water, but in order to pass from the watery exterior of the cell to the also-watery interior of the cell's cytoplasm where they are needed, they must first find a way to traverse the cell's oily membrane barrier. And they have evolved ion channels to perform this task. It is true that the first cells may not have needed ion channels because the first lipid membranes may have been inherently leaky on their own. It's also possible that small hydrophobic peptides evolved along with the membrane itself, and only later became the more complex ion channels we see today. However ion channels came about, nearly all types of cells we see today are highly dependent on the actions of these ion channels to transfer ions in and out of the cell. In fact, if it wasn't for mitochondrial membranes and ion channels, the use of ion gradients which are necessary for the production of chemical energy (ATP) and therefore life itself would be impossible.
One hundred years of work with cells by scientists in the 19th Century had provided the first hints of the prominent place proteins would soon assume in the search for clues as to how life works. By the mid-1800s, proteins in the form of "enzymes" were discovered by the chemist Bertholet and others to be necessary for the long sought explanation as to how the process of fermentation leads to the formation of alcohol from sugar, which is just one of many of the useful transformations enzymes perform. And up until the middle of the 20th Century, it was even assumed that proteins were responsible for carrying genetic information; due in large part to their ability for providing endless diversity; simply by varying the number and arrangement of their constituent amino acids (note: DNA would turn out to be genetic material by the early 1950s, not proteins). By the early 1960s, it was becoming clear that ion channels were composed of protein; and it came as little surprise to anyone. This is because it seemed reasonable to assume that in much the same way that a protein in the form of an enzymes was known to "help" chemical reactions along the chemical reaction pathway from substrate to product, protein ion channels could perhaps help ions back and forth thru the cell membrane by lowering the energy barrier inherent in this process. And as we shall see, this today is the generally accepted explanation for the mechanism of ion transfer from one side of the cell membrane to the other. Ion channels provide a pathway for the ion which is of lower energy, and therefore more favorable. This is not unlike the way in which water will always choose the path of least resistance when flowing from one place to another.
Below: Cartoon drawing of part of a cell membrane with an ion channel (purple) embedded in the membrane. On either side of the membrane is a watery environment. Ions, which are water-loving (hydrophilic) must pass thru the ion channel to go from one side of the cell to the other. This is because the cell membrane is hydrophobic (or "water-fearing").
By the 1830s, it had been determined by chemists that nearly all of the chemicals that make up living tissue were simply combinations of just a few non-metallic elements: carbon, hydrogen, oxygen, and nitrogen. Some proteins (proteins were actually first called "albuminous substances") also were found to have a small amount of phosphorus and sulfur thrown into their formulas for good measure. By the end of the 1800s, Emil Fisher was able to show that proteins were made up of various amino acids strung together like pearls on a necklace. He proved this simply by creating small proteins (called "peptides") in a test tube starting out with only a few types of amino acids and joining them together until they started to resemble proteins in the way they proteins were known to react to the "biuret" test. These artificial peptides he created looked and acted just like the albuminous substances, the proteins. By the 1920s, nearly all of the chemical structures of the 20 various kinds of amino acids which make up proteins were known, which meant that chemists could predict what kinds of reactions they could undergo, and whether they preferred being in water or in oily situations. Since the advent of x-ray crystallography in the 1960s, when it became possible to actually look at the individual atoms in a single type of protein molecule, it has been considered more accurate to think of the vast majority of proteins as being like strings of amino acids which fold up into a highly ordered "balls of yarn". Many of the 20 kinds of amino acids which have a tendency, chemically speaking, to be in oily hydrophobic environments were found on the insides of proteins more often than the outsides, and the rest of the amino acids were found to be in watery hydrophilic environments and tend to be found on the outside of proteins. It is also now known that the "domains" of ion channels that are embedded in and in contact with the oily hydrophobic lipids of the cellular membrane tend to be made out of the kinds of amino acids that tend to be found in oily kinds of environments. Some examples of hydrophobic amino acids are phenylalanine and valine. There are about 10 all together like this.
Amino acids which form the pore of the ion channel, the part of the ion channel where ions and water travel thru the membrane, because they are required to be in contact with water-loving ions, will of course tend to be the hydrophilic water-loving kinds of amino acids. Some examples of these are asparagine (first isolated from asparagus!) and serine. Like their hydrophobic amino acid cousins, there are also about 10 hydrophilic amino acids. An important question by the 1960s was: do the ions get any kind of help from the protein's amino acids as they travel thru the membrane? After all, ion channels have been shown time and again to be able to tell the difference between the different types of ions they let thru. For example, sodium channels let only sodium ions thru and potassium channels let only potassium ions thru. This means therefore that ions most probably are making some kind of physical and chemical contact with the protein ion channel as it traverses the membrane. But how? And does this have anything to do with "gating" of ion channels? In other words, how a channel opens and closes its pore?