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THINGS  ION  CHANNELS  DO

 

 

A dramatic example of the importance ions and ion channels have for living cells is often demonstrated by a classic experiment in freshman biology.    The students are first instructed to withdraw a small amount of blood from the end of their lab partner's finger with a sterile needle by stabbing it very quickly.    A single drop of blood is milked from the spot by massaging the tip of the finger and the drop is then placed gently on a glass microscope slide.   After several minutes watching hundreds or thousands of red disk-shaped cells (which are mostly red blood cells) streaming back and forth across the field of view of the microscope, the students are next told to add to the drop enough pure water to "swamp" the sample several times over in excess water.    When the students next look for the cells, many are surprised to find just how few of the cells are left intact on the slide.    Nearly complete devastation has taken place on a cellular level in a matter of minutes simply by adding pure water.   The explanation given to the students as to why all they now see are "chunks" of lysed, broken cells is because ions (mainly potassium, sodium and bicarbonate ions) could not escape the confines of the cell fast enough thru their respective ion channels to make up for the inrush of water which has an easier time moving thru the cell due to specialized water channels in the red blood cell membranes.   These water channels tend to always be wide open.     But the real reason that the water flows into the cell's interior is because of the presence of the trapped ions inside.    And only a limited amount of water can be added to the cell's interior before the membrane gives way and the cell bursts wide open.   

One of the principles of osmosis this demonstration clearly shows is that wherever ions are, water will tend to want to be also.   And this is the reason often cited by CF researchers as to how the loss of a chloride ion channel (CFTR) is able to cause the mucus lining the lungs of patients with this condition to become very sticky.    No functional CFTR means no ions moving thru the cell membranes of the lung epithelial cells from the cells and bloodstream to the lumen of the lung, which means no water can accompany the ions from the bloodstream thru the epithelium and do what the water is supposed to: help hydrate the mucus lining the lumen of the lungs.   The mucus therefore becomes very viscous, hard to remove, and an ideal environment for bacteria to colonize.           

Some ion channels in plant leaves have assumed the responsibility for the regulation of the volume of the cell and are able to open and close ("gate") their pores according to how much tension is placed on the cell membrane due to swelling or shrinking.   These channels, like most are grouped according to how they are regulated, and are therefore called  "volume-regulated" ion channels.    One reason they are needed is because if too much water enters a particular cell there is a danger the cell might burst.   Therefore volume-regulated ion channels will open and let their respective ions out of the cell when the cell expands in volume, which will have the combined effect of reducing cell volume back to normal.  This is because water from inside the cell will tend to want to travel to the outside of the cell right along with the ions, thus decreasing cell volume back to normal.    If the red blood cells in the above experiment had had volume-regulated ion channels which respond in this way by opening when there was an increase in cell volume due to water rushing into the cell, they wouldn't  have exploded.    Specialized cells on the outsides of plant leaves called "guard cells" depend on these kinds of changes in cell volume to control whether the stoma (a pore in the leaf designed to let in carbon dioxide) is open or closed.   This regulation is important because when the stoma is open for carbon dioxide, it also inadvertently lets water vapor leave the plant.    Here's how it works: when the plant has plenty of water, ions travel into the guard cells because specialized sodium and potassium ion channels will open and these ions will travel down their concentration gradient and into the cells.   This causes the cells to swell because water also flows in.   This causes the stomata to open and let carbon dioxide into the leaf.    It's interesting to consider the following fundamental difference between animal and plant cells:  Since animal cells have no rigid cell walls like plants have to help keep their cells from bursting (they can't have them for the simple reason that endocytosis is necessary for animal cells to eat), our cells must regulate water passage very carefully by more control and use of ion channels.      

One of the single most important processes all cells must carry out is called "intracellular messaging".   Intracellular messaging refers to the way in which a single cell is able to relay information from the environment around it to the cell's interior thereby leading to some kind of a change in either the metabolism or behavior of the cell.    An important signal that takes place inside many cells is an increase or decrease in the intracellular calcium ion concentration (Ca++).     Muscle cells, for example, depend on an increase in calcium ions in the cytoplasm which travel thru calcium ion channels in order to know when to start muscular contraction.     Changes in calcium concentration also is able to trigger an increase the process of "exocytosis", which is how many cells release material into their surroundings.   Exocytosis is crucial to the proper function of nerve synapse.   Nerve synapses allow the electrical signal from one neuron to travel to the next neuron.   This is a highly regulated phenomena and must take place quickly and at the right moment.   Another example of the importance of calcium ion channels in intracellular signaling is when a blood clot causes a stroke in the brain.   The cell death caused by the stroke is now believed to be due to the neurons in the brain "working themselves to death".   They appear to go into a kind of "metabolic overdrive" when intracellular calcium ion levels inside the cell increases at inappropriate times.   As the blood supply becomes unavailable to the brain during the stroke, it causes a loss of cell membrane potential across the neurons.  This presents a problem because neurons require a constant supply of oxygen in order to produce enough energy (in the form of ATP) to meet their needs, which is in turn needed to maintain ion gradients across the neuron cell membrane and keep the cell membrane potential high.    When these cells die therefore, they inadvertently release neurotransmitters such as glutamate, which then travels by simple diffusion to the nearby neurons and binds to their glutamate receptors.  Next, the cells respond to this high level of glutamate signal by releasing large amounts of calcium ions from within it's intracellular calcium stores by opening up the calcium ion channels in these membraneous organelles which reside inside the cell.   Since these type of neurons are "hardwired" to respond to high levels of calcium in their cytoplasm by increasing their metabolism, they eventually die probably of oxidative by-products which damage its cell membrane.   And still another important function of intracellular calcium ion stores is in vesicle fusion.   Vesicles are small spherical packets of membrane encapsulated cargos which are transported around in the cell's cytoplasmic interior.   At times, such as during a neurotransmission event, exocytosis of neurotransmitter-loaded vesicles is triggered by inrush of calcium thru channels.  

The first ion channels to be discovered and characterized were the voltage-gated ion channels, found in nerve and muscle tissue (see: history of ion channels).    These ion channels open and close (gate) in response to changes in the membrane potential, or voltage.    In order for neurons to conduct an electrical impulse, it is necessary for sodium, potassium, and calcium ion channels to open and close at the precisely the right times.     When the so called "action potential" travels along the neuron's axon, the membrane potential (voltage), which is itself the actual signal,  jumps quickly along it's length from a -70 mV inside the cell (compared to 0mV outside of the cell) to +50 mV inside the cell and then back to a normal resting potential of -70 mV again.     Another spectacular example of voltage-gated ion channel function comes from the electric eel.   This marine animal is capable of delivering several hundred volts of electrical energy at one time because of the specialized arrangement of the excitatory cells in its electric organ.   This unusual arrangement allows for amplification of the resulting ion currents across the cell membranes, not unlike the way a series of electric batteries connected together is able to deliver a large amount of electrical energy at one time simply by the turn of a switch.   This type of voltage potential in the electric eel is not restricted to electric fish.    For example, it has been calculated that just 20 human neurons connected end to end could deliver enough voltage to light up a small flashlight bulb (i.e. ~ 1.5 Volts).     

Ion channels are usually found on the surfaces of cells and are therefore easily accessible to most small molecules such as toxins injected into the blood and lymphatic fluid by venomous creatures like some kinds of snakes, scorpions, bees, among many others.     It is not surprising then,  that most animal venoms, tetrodotoxin from puffer fish for example, which are "designed" as protection for the animal,  bind to and specifically inhibit ion channel function in higher animals.   This inhibition can have dramatic and immediate effects on the functioning of muscle or nerve tissue and quickly render a perceived attacker unable to move or respond any further.   They have been used as natural anestetics for centuries by indigenous peoples.    Protein chemists have taken advantage of this high degree of specificity various toxins have to their respective ion channels in order to purify them from tissue sources.   The nAChR sodium ion channel was the first ion channel ever purified (in 1982).   This was accomplished by attaching the specific toxin for this ion channel to a stationary "matrix" on a chromatography column and then adding all of the thousands of different membrane proteins from the electric organ of Torpedo, a marine ray onto the column.   Since only the nAChR molecules will bind to the toxin on the column, it was possible to "wash thru" all the other proteins.   All that was left was the now-purified nAChR channels stuck to the column.   These nAChR ion channel proteins were then "eluted" (washed) from the column and in this way obtained in extremely purified form.     

The time-scale in which ion channels operate are very fast compared everyday human experiences.   Many ion channels are capable of allowing ions thru at the rate of 100 million ions each second, and many of these channels stay open less than a millisecond at a time before closing again.   This rapid rate of change which ion channels are capable of allows the cells, and consequently the organism itself,  a fine level of control over what goes in and out of a nerve or muscle cell, and how fast such exchange events occur.   Speed is often a very important factor for survival in nature because the amount of time it takes to respond to danger in the environment (i.e. the reflexes; which are muscles movements responding to nerve stimuli) can often mean the difference between survival or the alternative: death.   Since the proper functioning of nerve and muscle tissue is dependent on exchange of ions thru ion channels in the cell membranes, ion channel "kinetics" has evolved over millions of years to be very rapid indeed.

The Ligand-gated ion channels are channels which bind to small molecules responsible for other types of regulation.      These ion channels open or close depending on the presence of the type of ligand they bind to.   For example, there are sodium ion channels which bind to the neurotransmitter ligand acetylcholine and open; while at the same time, other sodium ion channels may close upon binding the same type of ligand.   In this way, a single ligand can regulate ion channels differently depending on where they are found in the body.     The nAChR ion channel is a sodium  channel which gets its name because it binds to the ligand nicotine (n) as well as the ligand acetylcholine (ACh) and is therefore functions as a receptor (R) as well as an ion channel.   There are also a host of ion channels which are gated by ligands found only in the insides of cells.  These are therefore named "intracellularly ligand-gated ion channels".  G-coupled protein receptors are capable of opening or closing certain ion channels indirectly by causing enzymatic cascades which result in ligand-formation (like cyclic-GMP) to take place within the cell.   These various ligands are then able to change the function of the ion channel directly by either opening or closing the channel.      Mechanical forces such as those which initiate the sensations of touch and sound can be converted directly into electrical signals when ion channel are activated directly by these signals, whereas ion channels which gate in response to light (vision) and smell (olfaction) must be activated indirectly by way of GPCRs.  It has been calculated that the ion channels in hair cells in the inner ear are capable of opening and closing in response sounds by movement of the hair cell's cilia hair by a distance equivalent to that of a single atom's diameter.  This would be equivalent to the entire Eiffel tower in Paris swaying a distance equal to only the width of a person's thumb.    The first and so far only mechanosensitive ion channel of this type that has been identified and cloned is from the fruit fly Drosophila's sensory brittle neuron.

ATP-synthase is the protein complex which lets hydrogen ions into the mitochondria and makes ATP in the process.    No life is known to exist on this planet without the ATP manufactured by these protein/enzyme/ion channels.    

Given the importance of maintaining a constant chemical environment within the cell, it is not too surprising that ion channels have been shown to be involved in host defenses.   Defensins are small molecular peptide ion channels (peptides are very small proteins often less than 100 amino acids in length) modified to "punch holes" in cell membranes of bacteria and other pathogens and are found in extracellular fluids of mammals and other animals.    Bacteria and even plants also produce them to attack microbes.     Recent experimental evidence has shown that the protein Bcl-2, dubbed by some in the media as the immortality protein may form ion channels under certain circumstances in purified lipid membrane bilayers (liposomes).    Along these same lines, the Beta-amyloid plaque protein which plays some as yet unknown part in Alzeheimer's Disease has been shown effectively form a calcium ion channel and could provide the long sought after mechanism for the death of neurons in the brains of patients with Alzeheimers Disease.      

Eosinophil cells of the human immune system are able to express on their surfaces a wide variety of ion channels which play an important role in the regulation of cellular activity during protection from microbial invaders.    During eosinophil respiratory burst, for example, where the eosinophil attempts to kill an invading cell directly, the efflux of protons through its proton (H+) ion channels provides an efficient mechanism of proton release and charge compensation.

After certain egg cells are fertilized by a sperm cell, the egg uses ion channels (potassium, for example) to set up a change in the electrical polarization of the cell membrane.   This, in turn, somehow keeps other sperm which come along later from fusing with the egg and therefore protects it.   

 


 

Above:  a hypothetical eukaryotic cell, showing the outer cell membrane (purple) as well as an intracellular organelle membrane (endoplasmic or sarcoplasmic reticulum) (also purple).   Note that the calcium ions (gray) have a special place within the ion milieu of the cell.   Calcium ions are actually second messenger ions and have the dual ability to traverse ion channels as well as deliver a message to other ion channels, usually involving activation.      

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