Channelopathies

By Sarita Ballakur          8/7/12

Most things about ourselves are set and ready to go before we are even conscious. Life is a general predetermined package, waiting for a soul to spin it into gear. One of the things which is unique to each self is that person’s thought process. The brain is one of the most fascinating aspects of the extremely captivating human body. It is basically the CEO of the body, ordering its managers (the nerves) to direct the work needed to be done. Neuroscience, the study of the neural system, is one of the most mysterious and compelling fields of study. No one knows for sure how the central nervous system works, but science aims to understand more about it. In the MOSTEC program, run by MIT, students including myself are privileged to be exposed to such an interesting field of study. Part of our project is learning about a new branch of neuroscience called Connectomics, the study of the connections between the nerve cells in the brain, through a variety of activities, including reading the book Connectome by Sebastian Seung, a professor at MIT. Personally, this book was really intriguing and I was really impressed with the amount researchers and neuroscientists have understood about the CNS so far. One subject that was really captivating was the topic of neurological channelopathies, or diseases of the nervous system that result from an abnormality of ion channels in cells. Not only was the name really cool, but also the whole idea that diseases could spur from a small malfunction was very riveting. Therefore, I decided to make it my goal for the final essay to try and understand more about this type of condition.

In order to comprehend what channelopathies are, one has to understand their essence, the ion channel. The idea of the ion channel extends back to 1952 when British biophysicists Alan Hodgkin and Andrew Huxley described the hypothetical existence of some ion channel-like mechanisms in their work that won a Nobel Prize. (Nadeem.) In the 1970s, Bernard Katz and Ricardo Miledi confirmed the existence of these ion channels. This was soon followed by the Nobel Prize winning work done by Erwin Neher and Bert Sakmann who invented the “patch clamp” technique, creating more substantial, clearer evidence of the existence of these channels. (Nadeem.) Ion channels are integral proteins in the cell membrane, which means that they transfer signals between the cell and its surroundings. They consist of multiple subunits, each with a very similar structure but different characteristics.(Kullmann1.) The central pore of the channel is made up of alpha units, and the rest is made up of other sub units that have names from the Greek alphabet, such as beta and gamma. Alpha subunits usually determine the ion selectivity and mediate the voltage-sensing parts of the channel.(Kullmann2.) Therefore, a functional channel could just be made up of alpha subunits. In addition to these subunits, some channels have a structural configuration where some proteins act as a gate or a barrier which can be opened or closed by certain stimuli. Recall the basic biology concepts of passive and active transport proteins in the cell membrane. Ion channels can be either passive (called leak channels), where the gate is always opened, or active, where the gate can be opened or closed by certain stimuli.( Kullmann2.) Active ion channels can be further subdivided into voltage-gated and ligand-gated. As expected, voltage-gated channels react to changes in electric potential while ligand-gated channels respond to chemical interaction at a part of the channel. (Kullmann2.) In a cell, there are many types of ion channels ranging from the sodium ion channel to the aquaporin channel (which regulates water flow). In addition to the range of “ions,” there are a diverse number of different types of ion channels for each “ion.” For example, there are many different types of sodium ion channels that can vary from leak to ligand-controlled. Ion channels are essential to the everyday function of the cell and are crucial to maintaining equilibrium with respect to the cell’s surroundings.

Ion channels occupy a special place in the neuronal cell. They are the mechanisms by which signals are sent across nerves, the method nerves utilize across the human body to send messages. Two major functions of the ion channel during this process are the incitement of a phenomenon known as action potential, and the role of facilitating the release of neurotransmitters into the synaptic cleft. From an electrical perspective, action potentials are great sudden, short spikes (increases) in electric potential that occur in cells. At rest, neurons are at their resting potential, or an equilibrium electric potential change in values between the cell and its surroundings. For most neurons, this is around -70mV. When enough depolarizing (making the resting potential more positive) stimulus is given to reach a threshold point, an action potential will occur. (Byrne2.) Action potential and the restoration period afterwards are mainly controlled by the activity of the potassium ion channel and the sodium ion channel. When threshold is reached by depolarization, sodium ion channels that are normally closed open up, and this greater permeability of sodium ions forces more ion channels to open up, inciting the action potential cycle.(Byrne2) Soon after, the permeability decays back to its original value and most of the sodium ion channels close. In a similar manner, potassium ion channels undergo a cycle when depolarization happens, however these channels take time to activate. Therefore by the time the action potential reaches its peak voltage, sodium channels start closing while potassium channels open.( Byrne2) This allows the cell to repolarize and reach equilibrium. This is the end of the action potential cycle. Soon after action potential is over, the region excites a neighboring region to have action potential as well, so it spreads throughout the neuron. The second component to the movement of signal across nerves is the release of neurotransmitters, where the calcium ion channel occupies a major role. The calcium ions are believed to help produce a vesicle binding protein called synapsin, which helps the vesicle bind to the phospholipid bilayer membrane and release the neurotransmitters. (Byrne3.) The nervous system heavily relies on correctly-functioning ion channels in order to do its job, therefore as one can see, if a channel is mutated, it can seriously affect the process of signal-relaying.

A channelopathy is a condition that is due to abnormal ion channels. There are many varieties of channelopathies, but the most common one is a neurological channelopathy, where ion channels in neurons are damaged. There are an immense variety of channelopathies, since every little variation can lead to a whole different disorder. (Byrne2.) In addition, a channelopathy may cause an abnormal gain of function or a loss of function, depending on the type of abnormality of the ion channel. (Rose.) The first disorders that were recognized as channelopathies were inherited muscle diseases. The first indication of neurological channelopathies was discovered in 1995. Furthermore, these diseases can be acquired as well as inherited. Acquired causes of the disease include toxins produced by some fish, snakes, spiders, bees, snails, and insects. These toxins paralyze or incapacitate the ion channels. Another acquired cause can be something of autoimmune phenomena, where antibodies may start attacking the ion channels. For example, Lambert-Eaton myasthenia is caused by antibodies that act against the presynaptic calcium channel at a neuromuscular junction. (Nadeem.) Inherited defects in genes, of either the dominant or recessive pattern, can also create channelopathies. (Nadeem.) Various mutations of the same gene can give rise to a wide range of disorders and it has been shown that the genes are not unique to an individual (polymorphic) since the diseases tend to run in families. Expression of channelopathies varies as some mutations may occur after certain ages or in specific types of neurons. (Kullmann2.) Channelopathies are mostly associated with the chloride, potassium, calcium, sodium, and acetylcholine receptors. One of the most well-known channelopathies is cystic fibrosis. This condition is caused by mutations in a gene called CFTR, which controls the formation of the chloride channel. The defect in the chloride channel results in thick mucus that can lead to respiratory infection. (Nadeem.) Conditions that result from the impairment of the potassium channel often limit nerve excitability, therefore resulting in twitching of certain muscles of the face and limbs known as myokymia. (Rose.) Other potassium ion-related channelopathies include periodic paralysis (recessive trait), congenital hyperinsulism, and long QT syndrome (which affects cardiac repolarization). (Nadeem.) Some sodium-ion related channelopathies include aramyotonia congenital,  Guillain-Barre syndrome, Espisodic Ataxia (EA), and Paramyotonia Congenita. (Rose.) Calcium-related channelopathies include EA type 2, Malignant Hyperthermia, and types of paralysis. (Nadeem.) Acetylcholine receptors are ligand-gated ion channels that usually occur at neuromuscular junctions. Although there are many more ligand-gated channels, including those of glycine and serotonin, most ligand-gated channelopathies that neuroscience has discovered so far, has been involved with the acetylcholine receptor. (Kullmann2.) An example of an acetylcholine receptor channelopathy is Myesthenia Gravis, which is the gradual paralysis of skeletal muscles caused by the development of antibodies against this receptor. (Nadeem.)

Channelopathies are relatively new conditions, and much research at the present is devoted to finding out more about them. In fact, many researchers speculate that channelopathies could be the cause of many more conditions than presently known. Many new genetic disorders are being found to be caused by a defective channel. As expected, many pharmaceutical drug companies are turning their attention towards creating new drugs to target ion channel problems. So far, many channelopathies have responded positively to membrane stabilizing drugs and the specificity of ion channels allows the potential for targeted drug therapy. (Rose.) There is also an investigation into the links between epilepsy and channelopathies. Many believe that those two are related, and scientists are currently looking into their connection in order to gain a better understanding of general epilepsy. Looking more into the future, researchers hope to use the results from all these studies about channelopathies in creating new therapies.

I still find channelopathies as fascinating as when I first read about them. Sometimes I lose interest about certain subjects, but that did not happen with channelopathies. It is such a deeper subject than I could have ever imagined! To me, it’s absolutely amazing how little small defects can make such a huge difference. Of course, after learning all this information, I have a couple of questions. While reading through all the sources and information about channelopathies, I never really found out how scientists found out about the different subunits of the ion channels and what exactly those subunits are. Are all alpha units the same for every channel? What exactly are alpha, beta, and gamma subunits? That’s something that I would love to see research figure out soon. In our neuroscience project, we learned about how easily modified mice are used in neuroscientific research often in order to test certain things. Through my research, I learned that scientists also learn more about channelopathies through theses means. Are those the only methods that we have available? Is there any other way we can learn about the channelopathies? The manipulation of mice is a little sad to me, but then as the famous saying goes “no pain, no gain.” I hope that in the future we can create research techniques without causing much harm. I really believe that channelopathies and the research about them will lead to breakthroughs in medicine and scientific research. It is one of the future paths of neuroscience.

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