6 Ion Channels

What are Ions?

Before considering ion channels in greater detail, we need to clearly define ions. Although I have already been talking about ions, let’s review. Ions are atoms or molecules of atoms in which one or more of the atoms possess either fewer or more electrons than protons, creating a net charge, either negative or positive. There are many different ions in nature. Fortunately, we only need to pay attention to four: Na⁺, K⁺, Cl^–, and Ca²⁺. These four ions are responsible for essentially all of the signaling carried out by neurons.

Each ion is a unique atom, which creates some of its uniqueness (e.g. K⁺ is much smaller than Na⁺), but its most salient feature is its valence. This refers to its net charge. For Na⁺ and K⁺, the valence is plus 1.  For Cl^– it is negative 1 and for Ca²⁺ it is plus 2.  The ion’s valence determines how it will behave in an electric field. That is, what it will do in the presence of a voltage difference. More about this later, but for now you should know that positive ions will move from higher to lower voltage and negative ions from lower to higher.

What are Ion Channels?

I introduced ion channels in the previous chapter. Let’s now look at them in greater detail. As you might deduce, ion channels must be integral membrane proteins because they span the membrane and you might also assume that the membrane-spanning regions take on the shape of an alpha (α) helix. Recall that a stretch of ~20 hydrophobic amino acids in the shape of an α helix will cross the membrane once. Ion channels contain multiple membrane-spanning regions which arrange themselves in the membrane so that they form a channel or a pore through which the ion can diffuse.

The picture above is a representation of a voltage-gated Na⁺ channel. For our discussion, you can ignore the green structures. These are subunits that modify the function of the Na⁺ channel, but are not essential. The part of the protein in blue forms the ion channel. The blue cylinders, labelled S1 – S6, are each α-helices that span the membrane. Notice that they are part of a long string of amino acids that contains 4 similar domains (I, II, III, IV).  At this point, if you are really paying attention, you may recognize a problem. If membrane-spanning regions contain all hydrophobic amino acids, why don’t they scare or chase ions away? Hydrophobicity, whether created by lipids or proteins is still hydrophobicity and ions are like water on steroids, metaphorically speaking. They do not just have polar covalent bonds like water, they have a full ionic charge. What gives?

This question puzzled neuroscientists for many years until they figured out that the rule mentioned previously – that proteins must form an α-helix while in the membrane – has exceptions. Specifically, they discovered that the stretch of amino acids connecting S5 and S6 dips into the membrane and forms the pore through which ions pass. Mutations in this part of the protein, that is, changing just a few of the amino acids, can convert the channel to a K⁺ channel. The interactions between the channel and the ions that creates the selectivity filter take place in this pore loop.

In addition to selectivity filters, many ion channels also have gates. Just as gates on fences can either be open or closed, the gates on ion channels can either be open or closed. What causes these gates to open or close? I am glad you asked. There are three types of gates.

The first type are voltage-gated, such as in the voltage-gated Na⁺ channel we have just been considering. As the name suggests, these channels are opened (or closed) by changes in the voltage across the membrane. How can voltage do that? Well, as we will discuss in the next chapter, any change in the voltage experienced by an ion will cause the ion to move. If this ion happens to be an amino acid that is part of an ion channel, its movement, albeit slight, can be enough to open (or close) the channel. If you return to the schematic diagram of the V-gated Na⁺ channel above, you will notice that one of the membrane-spanning helices, S4, is marked with positive charge. Approximately every four amino acids in S4 contains a positive charge. Because of the arrangement of an α-helix, these amino acids line up on the same side of the helix and create a dense source of positive charge. Thus, a change in voltage across the membrane exerts a strong force on S4. The slight movement of S4 gets transmitted to other parts of the channel, resulting in an opening of the pore.  Mutations in S4 which remove the positive amino acids eliminate the channels sensitivity to voltage.

The second type is ligand-gated. The channel is opened (or closed) by the binding of a chemical, called a ligand in this case. This is how neurotransmitters act on target cells. By binding to a part of the channel that acts as a receptor, the channel responds by changing its shape and thereby either opening or closing. Just as with voltage-gated channels, the binding of the chemical (ligand) move the protein ever so slightly, but enough to open or close the pore.

The simplest type to understand are the mechanically-gated ion channels. The gates in these channels are opened or closed by physical pressure. That is, the gates are either pulled or pushed open by an external force. Such channels are found in sensory cells that respond to physical stimuli. For example, the tiny bug crawling up your leg right now is pushing on skin cells in your leg and this pressure opens up ion channels that activate touch sensory receptors. The activated touch receptors then activate neurons that carry the message up to your brain so you can respond appropriately by either swatting the bug away or gently moving it to a safe location (if you are a Buddhist monk).

Ion movement across a membrane

Ion channels control ion movement across the cell membrane because the phospholipid bilayer is impermeable to the charged atoms. When the channels are closed, no ions can move into or out of the cell. When ion channels open, however, then ions can move across the cell membrane.

Gradients Drive Ion Movement

Ions move in predictable ways. Concentration (chemical) and electrical gradients drive ion movement. The chemical gradient refers to the natural process by which a high concentration of a substance, given enough time, will eventually diffuse to a lower concentration and settle evenly over the space. Ions will diffuse from regions of high concentration to regions of low concentration. Diffusion is a passive process, meaning it does not require energy. As long as a pathway exists (like through open ion channels), the ions will move down the concentration gradient.

In addition to concentration gradients, electrical gradients can also drive ion movement. I will describe the proper way to think about electrical gradients in the next chapter.  For now, it will be sufficient to think of the electrical gradient as a force that acts on charged molecules.  Positive ions (e.g. Na⁺ and K⁺) are pushed down an electrical gradient, while negative ions (e.g. Cl^–) are pulled up the gradient.  The combination of these two gradients will be referred to as the electrochemical gradient. Sometimes the concentration and electrical gradients driving ion movement can be in the same direction; sometimes the direction is opposite. The electrochemical gradient is the summation of the two individual gradients and provides a single direction for net ion movement.

When Gradients Balance, Equilibrium Occurs

When the concentration and electrical gradients for a given ion balance—meaning they are equal in strength, but in different directions—that ion will be at equilibrium. Ions still move across the membrane through open channels when at equilibrium, but there is no net movement in either direction, meaning there is an equal number of ions moving into the cell as there are moving out of the cell.