Biology 202
2002 Third Paper
On Serendip

Many scientists enter the field of neuroscience with a desire to understand how the human brain functions to create our actions. Some take a large approach and study reactions to stimulus in live animals. This approach leaves us still wanting to know about things that aren't a result of an outside stimulus. Other scientists take the minimalist approach and start by studying the exact mechanisms of individual cells of the brain. But, what good does that do us for everyday life? There is also the approach of taking our knowledge of behavior from diseases of the brain. Would we have thought about how our brain regulates our moods if it weren't for the fact that some people experience depression, in which the regulation of mood goes amiss? Many of the disease have led us to a deep understanding of the chemical interactions in our brain and body. At a very broad level, and ignoring religious discussions, we can say that every part of our existence is a result of chemical interactions. Besides giving us our substance, chemistry also gives us a mode of communication throughout our bodies. In our brain a large chemical component is that of the action potential that is conducted along a neuron as a result in the changing permeability of the cell.

The axons of our neurons are the pathway for the communication that exists in our nervous system. This communication takes the form of an electric signal, also called an action potential. The action potential occurs due to a change in voltage across the membrane of the axon. The change in voltage is achieved by a change in the permeability of the neurons to the ions, Na+, Ca+, and K+.(1)The cell starts with a large concentration of potassium ions, K+, inside the cell, and a large concentration of sodium ions, Na+, outside the cell.

The action potential propagates down the axon due to openings and closing of different channels allowing changing of the permeability to the differing ions (10). Channels are proteins that span the membrane of the axon. These proteins have a structure so that they can be allow ions to flow through pores that are only open at the appropriate times. Some of the channels are opened and closed by other chemicals, while some are initiated by a change in the membrane potential. The phase, opened or closed, controls the permeability of the cell, and therefore the possibility of an action potential. Each channel has a very distinct role in which ions it allows in and out of a cell. Channels are called by the ion that they primarily let through. One of the most impressive aspects of these channels is the precision under which they operate. If they didn't all of our functions would not occur with the ease that we experience.

A potassium channel works to let in only potassium ions. Yet, sodium ions are smaller, and intuition would say that they would get in without a problem through a pore, which is big enough to allow potassium through. The selection occurs in the central of the pore. The helices that the channel is composed of have enough space between them to hold exactly 2 potassium atoms (11). Only one Na+ ion gets in for every 10,000 K+ ions. At the same time that the channel is very selective it also allows the K+ to flow through at almost the exact same rate as diffusion, 108 ions per second. This precision is beyond our human understanding, yet contained within our own person. See a picture (11). Our cells are smarter than we can ever imagine being?

Based on their amino acid sequence, all K+ channels turn out to have a very similar structure and basis of function. Potassium channels are not unique to any organism or cell. A particular K+ channel, which is greatly studied, is the voltage-gated potassium channel. This means that the channel opens in response to a certain voltage difference that occurs across the membrane. The channel is closed when the cell is at rest. Following inactivation the channel opens via a complicated mechanism, which scientists are still trying to decipher(7)(8). The specific voltage is that which occurs after the Na+ channel has opened and allowed a significant amount of Na+ to be released from the cell. So, the K+ channel is induced to an open state by a depolarization of the membrane potential. The K+ channel opens at the beginning of the repolarization, or after the depolarization has almost reached its peak. The opening of this channel allows K+ ions to flow outside of the membrane of the cell, bringing the voltage of the cell back down to its normal level. The K+ returns to the inside of the cell through a pump that exchanges it for Na+ so that there is little voltage change.

Knowing the structure of the voltage dependant K+ channel was the one of the first steps scientists took towards understanding the channel. Scientists have defined the subunits as being S1-S6. The S1-S4 lie on the outer side of the pore, and influence the pore defining helices, S5 and S6. These two pore-defining units are those that are common to all K+ channels Near the center of the channel is a water-filled cavity where some drugs, such as TEA, bind to block activation(3). This core is very important, because it is where the potassium channels are selectively filtered. Much potential for further work lies within this core. It may be possible that different variations on the K+ channel have slightly different structures within the pore that could lead to important drug interactions. Ideally the brain's K+ channels could be enhanced, for treatment of disease such as Alzheimer's, without affecting other K+ channels.

A portion of S4 is positively charged, and the change in the membrane potential change moves this portion, possibly even to the other side of the membrane. The closed state of the channel is more stable than the open state due to a series of hydrogen bonds in the protein structure (8). This is why such a strong energy change, such as the depolarization of the cell or interaction with another molecule is necessary to change the structure of the channel. The helix probably rotates around its inner axis, and slightly out of the membrane at an angle. This motion is comparable to that of a corkscrew which opens as if it had petals. The S4 is also in very close proximity to the pore-forming segments, S5 and S6. S4 connects directly to the S5. This is still being evaluated, but the current proposal is that the torque in the S4 is translated directly to S5 and indirectly to S6. This seems very probable because the gating of channels that aren't voltage-gated rely on a twisting in S6 to open the channel. The other possibilities are that the S4 rotates the pore-defining helices in a way similar to the way that gears work, or that it moves outward from the protein complex, opening the channel by a pushing action (5). Channels that aren't voltage-gated contain similar apparatus that respond to other changes in their environment, such as the appearance of another protein, or ion.

There are many differences that are recognizable between voltage-gated and non-voltage-gated channels. These differences help understand how the voltage-gated channel works. We have already discussed the fact that there are additional helices on the voltage-gated channels, and that there are minute differences in the structure of the pore-defining helices. Another important structure in a channel is the "residues" that line the helices. Residues are the amino acids that reside on the transmembrane surface (5). In non-voltage gated channels that residues only interact with the lipids of the membrane that surrounds them. In voltage-gated channels these residues also interact with the additional helices (2). This is beneficial because these residues can possibly show where the interactions are between the different helices. Mutants of the residues have been studied to see which ones change the voltage-sensing domain (2). . Some mutations have no or little affect, while some eliminate gating altogether.

I feel that it is important to note how quickly the world of knowledge on our K+ channels is changing. Just 2 years ago scientists were frustrated and confused about these channels a href="#2">(2), and now they are being used as a guide for studying other ion channels, and pore openings a href="#3">(3). There have been multiple experiments done to determine the structure of the channel through x-ray crystallography, flourometry, and mutagenesis a href="#2">(2) a href="#4">(4). The picture has been almost perfected. Mutations have been done to determine structures that have a big influence on the voltage sensing and gating properties of the channel. For example, Li-Smerin et al. did a series of 37 mutations on the pore residues that led to two groups that they call the major impact and the minor impact residues a href="#2">(2). They were defined as being major or minor depending on how great of an affect the mutation had on the functionality of the resulting channel. When the major residues were mapped on the structure the scientists could make references as to what kind of contribution the original residue had. This information can define where the important structures are for making drugs that interact with these pores.

Eventually there will be a lot of helpful medical advances coming out of the knowledge of this channel works. Many diseases, from depression to Alzheimer's could possibly be affected by further knowledge of the ion channels. Recently researchers found that a genetic mutation in mice caused a selectivity decrease in the K+ channel which resulted in Alzheimer's like symptoms a href="#12">(12). This could have very strong potential for further implications. Further knowledge about the deficit in Alzheimer's can aid us in understanding what the normal flexibility of the brain is a href="#14">(14). We know so far that this protein, which is invisible to the naked eye, may hold our potential for learning. Mutations to the protein alter its response to voltage changes, and therefore the potential to propagate an action potential. The possibilities are endless, and the knowledge is fast approaching. But, it is without a question that the K+ channel is inescapable in its importance to our behavior and existence.

References

1)Serendip Notes, Some notes are available from the class on the Neurobiology of Behavior which discuss Action Potentials.

2)A Localized Interaction Surface for Voltage-Sensing Domains on the Pore Domain of a K+ Channel

3)Potassium Channel Mechanics

4)Reconstructing Voltage Sensor-Pore Interaction from a Fluorescence Scan of a Voltage-Gated K+ Channel

5)Taking Apart the Gating of Voltage-Gated K+ Channels

6)Reconstructing Voltage Sensor-Pore Interaction from a Fluorescence Scan of a Voltage-Gated K+ Channel

7)Tight Steric Closure at the Intracellular Activation Gate of a Voltage-Gated K+ Channel.

8)9)Visual of the K+ Channel

10)Lights, Camera, Action Potential, A site made for children that has great descriptions and visuals of an action potential.

11)3-D Image of Potassium Channel

12)Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities

13)The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity

14)Linda M. Boland, Ph.D


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