Approximately 30,000 Americans have a disease called Cystic Fibrosis (CF). This is a genetic disease that an individual inherits from both parents and suffers from throughout their lives. People with CF have serious respiratory and digestive problems because they build up a viscous, sticky mucous in their lungs and other organs. Just a couple of decades ago, most individuals with CF did not survive long enough to begin kindergarten. Fortunately, medical research has pushed the average lifespan of a CF sufferer to approximately 35 years. In addition, the root cause of the disease has been identified: The plasma membranes of cells in the affected organs are missing a key component and so do not function properly.
The plasma membrane (also called the cell membrane) is anything but a simple barrier between the inside of a cell and the environment outside of it. As explored in Membranes I: Introduction to Biological Membranes, there is a wide variety of embedded components that are essential to the life of the cell, including lipids, carbohydrates, and proteins – many of which regulate what is allowed to pass into and out of the cell (Figure 1).
The plasma membrane: A selective barrier
The plasma membrane of all cells is a barrier to most molecules. Only uncharged, non-polar molecules can easily pass through the membrane. Non-polar molecules are those whose bonds involve equal or symmetrical sharing of electrons so there are no partial positive or negative charges. This includes gases like carbon dioxide and oxygen and a few lipid hormones like testosterone and estrogen.
However, most molecules in our bodies are either charged or polar. For example, water cannot pass directly through a biological membrane because it is a polar molecule, with partial positive and partial negative charges. The interior environment of the plasma membrane is highly hydrophobic because of the close crowding of all of the fatty acid hydrocarbon tails (see Membranes I: Introduction to Biological Membranes). Those hydrocarbon tails are filled with non-polar bonds, and there are essentially zero polar bonds anywhere in the interior section of the membrane. This creates a very hydrophobic environment, and thus water is strongly repelled.
Glucose is another example of a polar molecule that cannot easily pass through the membrane. It is much larger than water with many polar bonds all throughout the molecule. Ions, such as sodium (Na+) and chloride (Cl-), have an even more difficult time going through the membrane than glucose. They are not just partially charged; they are fully charged and thus strongly repelled by the interior of the membrane (see Figure 2).
However, we also know that water, glucose, sodium, and chloride move in and out of cells all the time, which means that there must be something that assists them. This “something” is a collection of transporters: both passive and active.
Passive and active transporters
There are transporters embedded in every cell membrane that allow molecules to pass through. In Membranes I, we discussed the water transporter, aquaporin – but there are many more of these transporters within the membranes of all living cells.
Transporters are proteins that are divided into two classes: passive transporters, also called channels, and active transporters, also called pumps. The difference between active and passive transport is whether or not energy is required to move the molecule from one side of the membrane to the other. A channel is passive because it does not require energy to help molecules flow through it. (The aquaporin water transporter is a channel.) Pumps, on the other hand, do require energy to do their work, so they are called active transporters.
Channels: Passive transporters
In order to function, the heart, nerves, and muscles in a body need to move sodium ions into and out of their cells. However, because sodium ions are charged and cannot get through the membrane directly, cells have a sodium channel that creates a path – a tunnel – through the membrane where ions can flow freely.
Because channels merely provide a path for molecules to flow, they are only capable of allowing those molecules to flow from where they are in high concentration to where they are in low concentration. In other words, channels allow specific molecules to diffuse when they otherwise couldn't because a membrane is in their way. When a channel helps molecules to move through a membrane, this is called "facilitated diffusion." The molecules are passively spreading out evenly, but they are getting a little help from the channels to do so (see Figure 3).
For example, inside of human cells, there is a fairly low concentration of sodium ions, but outside of the cells, in the general fluids of the body, there is a high concentration of sodium ions. This is why tears, sweat, and other body fluids taste salty. Thus, surrounding every cell of your body, there is a concentration gradient of sodium ions – low sodium inside of the cells and high sodium in the surrounding fluid. Channels can allow only the passive flow of molecules down their gradient (from high to low), not the other direction, so a sodium channel would allow sodium ions to flow into the cell, not out of it.
Channels are important for many different types of molecules. In 1989, it was discovered that the basis of Cystic Fibrosis was the lack of a specific kind of passive transport channel in the cell membranes of CF patients. This channel, known as CFTR (Cystic Fibrosis Trans-membrane Conductance Regulator), is actually made in the cells of individuals with CF, but it lacks just one tiny piece: an amino acid in a crucial location. Because of this one tiny alteration in its structure, CFTR is never delivered to the plasma membrane where it would normally allow chloride ions to flow out of the cell (Cheng, et al., 1990). A CFTR channel is shown in Figure 4.
The flow of chloride ions from certain cells in the lungs is essential for making mucus of the proper consistency. Without chloride, the mucus is not as watery as it should be. When chloride fails to flow out from the cells of CF patients, viscous mucous builds up in their lungs, leading to the symptoms and infections associated with CF, such as frequent coughing and wheezing. This underscores how important a job the cell membrane plays. It is much more than a static, selective barrier.
Some channels have gates
Many cells, especially neurons and muscle cells, have sodium channels on them, but these are usually held closed by gates. These gates prevent sodium from rushing into the cell so that the gradient can be maintained. However, these gates can also be opened at specific times. Because sodium concentration is higher outside the cell than inside, if the gates on the sodium channel suddenly opened, sodium ions would begin to flow inward.
It is important to remember that molecules move in random paths. While molecules will flow in through the channels from outside the cell, some will also flow back out. It’s just that more ions will flow into the cell than out of the cell because there are more ions outside to start with. Thus, when the gates open, we say that there is net movement of sodium ions into the cell. If the gates were to stay open long enough, the concentration of sodium inside and outside would equal out. There would be no more gradient and no more net movement. This doesn’t actually happen, though, because the gates only open for a brief instant.
Pumps: Active transporters
How do sodium ions get to be at a high concentration outside the cell in the first place? To answer this, we must consider the topic of active transport. Active transport is exactly the opposite of passive transport. First, it does require the input of energy, rather than relying on the random motion of molecules (and this usually comes in the form of ATP). Second, active transport builds concentration gradients – meaning that it increases the concentration of molecules in a given area – rather than reducing them (see our Diffusion I: An Introduction module). Third, it requires the action of a membrane pump (instead of a channel) to move molecules from one side of the membrane to the other.
Membrane pumps are proteins embedded in the plasma membrane that pump specific molecules or ions into or out of the cell. For example, there are proton (H+) pumps in the lining of the stomach. They pump protons into the stomach cavity, creating a very acidic solution to help digest food (Figure 5). People who suffer from chronic heartburn or indigestion might take Nexium, Prilosec, or Prevacid to treat this discomfort. These drugs work by slowing down the proton pumps in the stomach walls and thus making the stomach less acidic (Peghini et al., 1998). Other examples of pumps are the calcium (Ca2+) pumps in the intestines that help absorb calcium from food, and the glucose pumps in the kidney that grab all the glucose out of the pre-urine fluid so that we don’t lose glucose constantly in our urine. Unlike channels, all of these pumps must use energy to do this pumping.
The sodium/potassium pump
Perhaps the most important pump of all is the sodium/potassium pump, usually written simply as the Na+/K+ pump. This pump exists in just about every cell membrane of the human body, and indeed in almost every cell membrane of every animal that has ever lived on Earth. This pump is responsible for pumping sodium out of the cell and potassium into the cell. Because it pumps two things in opposite directions, it is called an antiport.
Although there is already a lot of Na+ outside the cell (and very little inside), the Na+/K+ antiport actively pumps Na+ from inside the cell to the outside. The same is true for potassium (K+) – it actively pumps K+ into the cell despite higher concentrations within than without. The antiport is constantly building both gradients by increasing the concentrations of sodium outside of, and potassium inside of, the cell. The Na+/K+ pump works tirelessly on every cell of the human body, constantly maintaining these two crucial gradients (Figure 6).
Because it is working against the natural flow of diffusion – to balance out the concentration on either side of the membrane – the Na+/K+ pump is said to be engaged in active transport, a process that requires energy. Like most work that cells do, the energy for this transport work comes in the form of ATP.
Why is it so important to keep the interior of the cells low in Na+ and high in K+? The reason is because these two gradients are used for all kinds of important purposes around the body, such as allowing nerves to send messages and muscles to contract. The plasma membrane of neurons and muscles have sodium and potassium channels on them; however, these channels are not always open – they have gates on them that are usually closed. These gates can be suddenly opened, though. For example, muscle cells have a sodium channel with a gate that can be opened by the neurotransmitter acetylcholine. If a neuron suddenly releases acetylcholine onto a muscle, the gate on the sodium channel will swing open. When that happens, sodium ions will then rush into the cell because of the ever-present sodium gradient. The sodium ions (Na+) then cause a rapid chain reaction that leads to muscle contraction. (See Figure 7.)
During normal muscle use, the influx of sodium is temporary and is quickly reversed by the Na+/K+ pump, which is always working to re-establish the gradients as quickly as possible. However, during strenuous exercise, particularly when the muscle is not accustomed to such demanding work, the Na+/K+ pump and other ion pumps that are important in muscle cell function cannot keep up with the ion influx from the gates being opened so much. This leads to a sustained and involuntary contraction of the muscle, also called a cramp, as the sodium ions build up inside the muscle cells. Because the contraction is involuntary and very intense, cramps are painful and usually debilitating. The only way to reverse them is to stop all exercise and massage the muscle, coaxing it into a relaxed state and giving the Na+/K+ pump a chance to get caught up on its job of getting sodium out of the cell, and potassium in. Athletes who are in very good shape have fewer problems with cramping because their well-trained muscles have more Na+/K+ pumps, and other ion pumps, than the rest of us have.
Many neurons in your brain also respond to a sudden influx of sodium ions by releasing neurotransmitters onto neighboring neurons. The crucial importance of these sodium channels is underscored by the fact that some of the most deadly poisonous compounds ever discovered are compounds that block sodium channels, paralyzing nerves and muscles. Tetrodotoxin, one such sodium channel-blocking poison found in Fugu pufferfish, is 100 times more lethal than cyanide. Ingesting even a very small dose of tetrodotoxin can completely paralyze someone by preventing both muscles and neurons from functioning (Narahashi, Moore, & Scott, 1964).
Discovery of the Na+/K+ pump
In the 1950s, scientists knew that ions move in and out of cells and that, because of this, cells had a voltage – a difference in the charge inside of the cells compared to outside the cells. The voltage, also called the resting membrane potential, of nearly all cells is negative – meaning there are more negative charges inside the cell than positive ions. This internal negative charge of cells mostly comes from many of the large macromolecules of life – DNA, proteins, lipids, and sugars – which are all negatively charged. But scientists didn't understand how the cell prevented positive ions from flowing in to cancel out the negative charges, or why all animal cells maintained a low concentration of sodium and a high concentration of potassium.
This changed in 1958 when Jens Skou, a Danish physician, made an accidental discovery while studying how local analgesics worked. Analgesics are substances that prevent or reduce pain; an example of a local analgesic is Novocain, which is used by dentists to numb the mouth during oral surgery. In his laboratory, Dr. Skou noticed that cells have an enzyme embedded in their membrane that consumed a lot of ATP. He then noticed that when he exposed cells to some analgesics, the membrane-bound enzyme stopped consuming ATP, as if it were paralyzed. The effect would slowly wear off as the drug washed away from the cells. The crucial part of the discovery came when he noticed that the drugs didn’t only affect the mysterious ATP-consuming enzyme, but also allowed sodium to build up in the cell and potassium to leak out. No other ions were affected – just sodium and potassium. And once again, the effect wore off over time. With exactly the same timing, the ATP consumption would gradually resume and the Na+ and K+ gradients would be restored. Dr. Skou didn't immediately make the connection and went about studying other painkillers.
It was only after a conversation with another scientist, Robert Post, who was studying sodium transport in red blood cells, that they both realized they could be studying the same enzyme. Dr. Post went back to his lab and tried the same analgesic that Skou used, and it worked – it inhibited sodium transport in the red blood cells. Meanwhile, Skou telephoned his laboratory and instructed them to try the drug that Post had been studying, ouabain (pronounced wah-bain), and a few days later, his laboratory called back to say that it worked the same way (Skou, 1965).
What does inhibiting a sodium/potassium pump have to do with relieving pain? As mentioned above, the gradients of sodium and potassium are crucial for the functioning of neurons. When ouabain and other analgesics slow the Na+/K+ pump on the sensory neurons responsible for sensing pain, they temporarily disrupt the Na+ and K+ gradients. When this happens, the neuron is paralyzed for a while and cannot transmit its message of pain to the brain. Though the Na+/K+ pump is on every cell of the body, these drugs do not affect other cells as powerfully as they do neurons. Most cells don’t rely as much on the Na+ and K+ gradients to function, so these cells are not as affected by the drugs. However, there is one other type of cell that is affected – muscles. Both muscles and neurons are said to be excitable, which means that they are very sensitive to changes in voltage and movement of ions. Drugs that inhibit the Na+/K+ pump can paralyze muscles as well as neurons.
In summary, cellular membranes are neither passive sacs around the cell nor solitary cell parts. Embedded in the membrane are proteins that perform vital functions for the cell. Among the most important functions of these proteins is the transport of various molecules into and out of the cell. As we saw with Cystic Fibrosis, when even just one of the hundreds of transporter types in a cell membrane malfunction, serious disease can result.
At the same time, the functions of these transporters can sometimes be manipulated with pharmaceutical drugs to treat certain medical conditions. Drugs that restrain the proton pumps on the stomach lining are useful in treating acid reflux, and drugs that inhibit the Na+/K+ pump can act as topical pain relievers. Thus, many biomedical scientists study plasma membranes in their pursuit for treatments and cures to common medical conditions.
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