Distribution of amino acids making up an ion channel in a membrane (above):    The lipid membrane bilayer is hydrophobic in the center (gray) and hydrophilic on the surfaces (blue).    Ions (black) can only pass thru the pore of the ion channel because this is the only part with hydrophilic amino acids lining the pore  (green = area of ion channel with hydrophilic water-loving amino acids).   The rest of the ion channel mostly consists of hydrophobic amino acids (purple).  



What forces might come together for the purpose of guiding an ion up to and thru the pore of its respective type of ion channel?      The answer appears to involve a special kind of chemical and physical interplay, almost like a dance which takes place on the sub-molecular level, between the ion and the pore of its channel; where the distances are measured in terms of millionths of a millimeter, rather than everyday macroscopic distances we tend to be used to. Consider the following admittedly rough analogy:    Imagine that you have just fallen to the bottom of a deep well, and at first it appears that the only way you can climb out of this well is by scaling up the sides of the walls to the surface.     Since it is dark down there, you find you must first feel your way around the sides of the well, grasping at anything that might attract your attention.     It is at this point that you touch what feels like the bottom rung of a ladder; and you hold tightly onto it.    Your actions would be similar to the way in which a negatively charged ion is attracted to a positively charged amino acid (for example, lysine) on the exterior of the ion channel near the opening of the pore.    This type of interaction is electrical (negative attracted to positive charge) in nature and it serves to increase the "effective concentration" of these ions near the outside of the pore (don't worry if you didn't understand that completely. Freshman chemistry would help a lot here, though).     

Next, you guide your feet onto the first rung of the ladder and you place your hands onto the next rung above in it order to pull yourself up towards the surface.     But the hole becomes smaller as you go up and you find you need to shed the heavy jacket you are wearing in order to squeeze thru.     In much the same way, an ion must often times shed the water molecules which surround it before it enters the pore (note that these dozen or so water molecules are always there surrounding the ion whenever the ion is in the watery liquid environment outside or inside the cell).    It is unfavorable, energetically speaking, for an ion to lose its water molecules, so as the ion sheds itself of the water molecules, what needs to take place at the same time is for the amino acids composing the ion channel pore to make up for this energy cost by forming the same type of bonds (called "hydrogen bonds") with the now naked water-less ion just as if these amino acids were themselves the water molecules.     Amino acids such as serine and threonine "look" enough like water, chemically, to take water's place in some proteins.     In the same way, the oxygen-studded peptide backbone of the protein can help to take the place of water somewhat as well since water is also composed of oxygen.       

Anyway, you continue your climb up the ladder, rung by rung, until you start to tire out. As for the ion in the channel, it is using "chemical rungs" formed by the ion channel's amino acids and the peptide backbone of the channel in order to guide it and keep it moving in the right direction.    Together, they form what are called "noncovalent bonds" which are much weaker in nature than the kinds of bonds that hold atoms together as in a molecule (i.e. "covalent bonds"), but added together these hydrogen bonds are of considerable influence on the now dry ion.   As you continue climbing, you notice that the diameter of the hole you are climbing out of would preclude someone larger or smaller than yourself from fitting thru, because someone too big could not fit thru the hole, and someone too small wouldn't be able to navigate the rungs of the ladder correctly.     Similarly, the ion channel is able to select the proper type of ion it needs to let thru it (called the "selectivity filter").    For example, it isn't unusual for a potassium ion channel to let thru 10,000 potassium ions before it will let a single sodium ion thru, even though both might be present in the same amount near the outside of the pore.    

By the time you reach the halfway point,  you are tired and need a rest.    Very hard to do on a ladder. Fortunately, the hole you are climbing out of has a small platform for you to rest on at the halfway point.   This would be analogous to the "energy well" that an ion falls into in order to keep it moving thru the channel and in the right direction. An example of an energy well for a negatively charged ion would be the presence of a positively charged lysine amino acid,   just like the one on the outside of the pore, placed this time strategically in the middle of the pore by the ion channel protein (this kind of ion platform is sometimes called the "vestibule" of the ion channel.    CFTR is believed to have one just on the intracellular side of the middle).    This vestibule acts like insurance so that once inside the pore, the ion will keep moving thru in the right direction, and not get stuck in the middle or diffuse back out the way it came.   

Back to the analogy. At this point, following your rest, you sense the presence of a second climber beneath you. Not wanting to hold the second climber up,  you keep moving towards the surface.   This second person therefore has the effect of keeping you traveling out of the pit.    So too, with some ion channels a second ion is often allowed into the pore behind the first one and essentially gives the first ion enough of a nudge (electostatically speaking) to keep it moving in the right direction. This is because both ions are of the same charge (positive or negative) and these like charges repel, or push on each other.     Both you and the ion are now all the way thru to the other side and diffuse into the solvent, or walk away, depending.

In Summary then, ion channels are proteins (or more often groups of proteins made up of individual "subunits") which reside imbedded within the lipid bilayer membranes of cells and some viruses, where their job is to regulate the passage of small charged molecules (ions) in and out of the cell or it's various organelles.    Because it takes approximately 20 times more energy for an ion to pass thru a lipid membrane bilayer compared to an uncharged water molecule, ion channels and pumps are necessary for transport of all charged molecules thru cell membranes.    During the latter half of the 20th Century, it has even been conclusively demonstrated by biochemists and structural biologists that ion channels have an even finer level of structure than first imagined, and are composed of distinct regions which act as a kind of molecular "division of labor".    For example, one part of the protein forms the pore where ions pass, while other parts (also called "domains") are responsible for opening and closing of the pore.    There are also domains which have the ability to interact with the lipid membrane in an energetically favorable way as well as domains which may bind certain regulator molecules (called "ligands") and have the effect of influencing the activity of their specific ion channels.   Next we will look at some of the physiological reasons ion channels exist in the first place, and try to understand why their absence or failure to operate properly can lead to diseases like cystic fibrosis.  

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