How ion channel selectivity is established
No matter which body system you study, ion channels will play a big role in its physiology. It does not matter whether it is skeletal muscle, heart, nervous system, kidney, or any other tissue. The physiology always relies upon which ion channels in the cell’s membrane are open and which are closed. Because each membrane ion channel allows only one type of ion to pass, this post will focus upon how ion channels recognize a difference between sodium ion (Na+) and potassium ion (K+).
Biologic membranes are composed of several types of fat (lipid) molecules. Water soluble particles such as electrically charged ions do not pass through these membranes without help. A channel for ions must be inserted into the membrane that is open to the fluid on both sides.
The interior of the channel must be able to attract the ion. That is, it must be lined with molecules that carry a partial charge that is opposite the ion’s charge. Also, the channel core must be just large enough for one type of ion to pass.
Membrane ion channels consist of proteins that assemble themselves in various configurations. Somewhere within each protein channel there is a selectivity filter so small that only one type of ion can pass.
Proteins have characteristics that make them especially good channels. First they can form spirals (helices) with their lipid soluble parts on the outside to fix them into cell membranes. The opposite side of the spiral can be made of polar amino acids that have a partial electrical charge to attract ions. Second, proteins change their shape readily when they encounter fluctuations in the electrical field surrounding them. Their ability to change their shape allows the channel they form to open and close. Opening and closing of ion channels is a major form of cellular communication.
Two very important ion channels found in the body are the channels for potassium (K+) and sodium (Na+). The molecular weight of sodium (~23) is less than that of potassium (~39). Both ions carry a single positive charge, and the space occupied by a Na+ ion is less than that occupied by a K+ ion. So, why do smaller sodium ions not pass through the selectivity filter of potassium channels? It is only very recently that scientists solved this mystery.
The K+ ion channel is an excellent example of how a protein channel can be ion selective. Ions in water solution are bound loosely to water molecules. This arrangement is called a hydration sphere. An ion hydration sphere is much too large to fit into the passage of an ion channel. So first the water must be removed. To strip water molecules away, an ion must meet another molecule with which it can form a bond that is stronger than its bond to water.
Structural analysis of K+ ion channels from a variety of species demonstrated that they are lined with carbonyl oxygen. Carbonyl oxygen, oxygen double bonded to carbon, can be found in the carbon backbone structure of all proteins. The position in space of a protein’s carbonyl oxygen varies depending upon how the protein is folded in upon itself. In the potassium channel the carbonyl oxygen, with its partial negative charge, is in exactly the correct position to compete with water for the potassium ion (K+) at the entrance to channel.
The potassium channel illustration shows the entrance to the potassium channel looking down from the top with a single K+ (purple dot) inside. Notice the red oxygen molecules surrounding the purple dot. The illustration is based upon data for this channel in the Protein Data Bank, file number 1BL8.
The same process does not work for Na+ at the K+ channel, because Na+ ion is smaller than K+ ion. The carbonyl oxygen moieties lining the K+ channel opening are too far apart to form a competitive bond with the smaller Na+ ion. With its hydration sphere still in place, Na+ is much larger than a bare K+ – much too large enter the potassium channel. For more about how water hydrogen bonds with itself and with other charged or polar molecules you may also want to read “Water’s Chemistry Governs Physiology”. Or, you may want to check out “Physiology: Custom-Designed Chemistry”.
Each ion channel has its own mechanism for permitting entrance of only one ion. The potassium channel is one example. As you probably guessed, the sodium channel has an entirely different configuration than the potassium channel because it uses different protein features to achieve its selectivity.
A voltage sensitive Na+ channel of the brain consists of one large protein that works with 2-3 smaller proteins. The large protein contains the ion conducting channel. It is regulated by the presence of one or more of three smaller proteins. Each of the smaller proteins is about 10-15% of the size of the large protein. Presence of the smaller proteins sometimes alters the cellular location of the larger protein and sometimes alters its voltage sensitivity.
The diagram presented above illustrates the sections of the large protein subunit of a voltage-gated sodium ion channel. The protein structure is spread out in a membrane to model its detail. In this diagram N is the beginning of the protein’s amino acid sequence and C is the end of the sequence. G is where sugars have been added to the protein. P are the sites where the protein can have phosphate groups added. S is the location of the ion channel components. I are the sites affected when the channel is inactivated and Na+ cannot enter.
In reality the four sections, labeled I-IV in the picture, form a circular cluster in the cell membrane. Ion selectivity for the Na+ channel is created by the protein loops between the helices labeled 5 and 6 in each of the four sections. Each of these loops is on the outside of the membrane. As the four sections of the channel group themselves together in the membrane, the four large loops between helices 5 and 6 interact with each other to create the selective channel for Na+ ion. As with K+ ion at the potassium channel, water is stripped from Na+ ion before it enters its channel. The inner opening of the Na+ ion channel is formed by the combined 5 and 6 helices of all four sections. The area between helices 5 and 6 on the inside of the membrane are open to the inside of the cell.
Predicting the cellular effects of ion channel opening and closing is a challenge for most students. I will write more about that subject in upcoming posts.
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