After a week of asking questions and asking the same questions again, the mystery of what the Akt/GSK3 pathways does for us has become a little clearer. Despite all of the questions I cannot answer related to this topic, I can say with confidence that many biological functions that rely on the activation of dopamine and G-protein coupled receptor’s signaling. I have also learned that the Akt/GSK3 pathway is important to neurological well-being and is a factor in many diseases. The article combines these pieces of information by informing us that the Atk/GSK3 pathway is controlled by a G-protein coupled receptor, and by manipulating that pathway there are changes in neural behaviors. However, it is still uncertain as to where in the pathway it is most beneficial to inhibit signaling in order to treat various diseases. With the discussion of this article it has also been established that there is still a lot to learn with the pathways of pharmaceuticals and just how selective these drugs are. This article helped us explore one pathway that is affected by dopamine receptors and how it could be affected various diseases.
I now have a better understanding of this particular pathway, but unfortunately this is only a very small piece to the puzzle to understanding the connections between pathways of neurological diseases, as well as the medications that are prescribed to help “fix” these diseases. The Akt/GSK3 pathway is only one pathway that is influential in diseases, but there is a lot of research that needs to be done to make sure pharmaceuticals are only acting on what they are supposed to.
At the end of the day, the past week has been informative and has opened my eyes to how much is unknown within our brains. I realize that a lot of that has to do with my own novice understanding, but I believe there is so much happening within the brain that progress with this type of research will take scientists a long time to quantify and actually make it useful to the public.
Akt and GSK3: Not Just Two Acronyms Someone Uses in a Lab
This week in class, we discussed the Akt-GSK3 pathway. The obscure name is enough to make most readers click on or scroll down, but before you do, I recommend you read just a little bit further. This pathway affects many aspects of your life and probably plays a role in a condition affecting someone in you know or maybe even you personally. The following list provides some examples of conditions associated with the Akt-GSK3 pathway:
- Addiction
- Parkinson’s Disease
- Schizophrenia
- Bipolar Disorder
- Depression
It’s incredible that one pathway can be implicated in and targeted for treatment for so many problems. Research into this pathway can lead to many important findings, improving the lives of many people in the process.
Research on the Akt-GSK3 pathway began when scientists found lithium to be an effective treatment for bipolar disorder. Lithium acts to disrupt GSK3 signaling inside the cell. Inhibiting of GSK3 activity has a variety of effects in the brain. Among them is the inhibition of serotonin-inhibiting receptors. Serotonin levels are often decreased in major depressive disorder. Antidepressants (specifically a class called SSRIs) act to increase the levels of serotonin in the brain. Inhibiting GSK3 has a similar effect to these SSRIs; therefore, lithium acts to decrease the lowness of the down periods in bipolar disorder. More selective GSK3 inhibitors are also being developed as depression treatments.
In schizophrenia, many atypical antipsychotics exist, but nearly all of them have the ability to act on the same class of receptors called D2-receptors. While it was thought this was the primary means of affecting psychotic behavior, it has been shown that other pathways are affected by these drugs. It is unknown whether the initial affected pathway, the newly-discovered affected pathways, or a mix of both cause the effects of antipsychotics. With further research, it may be possible to isolate a more specific target, producing more efficacious treatments with fewer side effects.
In Parkinson’s, the Akt-GSK3 pathway may contribute to brain cell degeneration, though the mechanism for this is unknown. Researchers discovered this link by examining the cellular effects of the neurotoxins used to create Parkinson’s-model rats in the laboratory. Further research into this pathway could be used both to treat and hopefully prevent or delay the onset of Parkinson’s disease.
Dopamine has been known to be an active part in the physiology of addiction. All reinforcing stimuli facilitate the release of dopamine in a certain part of the brain. Dopamine also acts on D2-receptors which, as stated previously, affect the GSK3 pathway. It is unknown whether addictive substances exert their effects through the Akt-GSK3 pathway or whether activation of this pathway from additional dopamine is merely an additional effect. It may be worth examining this to see if addiction can be curbed or even prevented in the future.
One other important thought we examined in our discussion is development of these new pharmaceuticals. It is important for them to be specific enough so as to avoid side effects, but also broad enough to address enough symptoms as they can. Also, a drug must be able to get to its target, which further complicates the process for researchers. Modern medicine is capable of many things, but innovation takes time and money. The human body also creates obstacles because not every drug can make its way into the brain or can be absorbed fast enough to provide relief. These concerns must be addressed when designing drugs.
Those are the facts we currently know. Facts, however, should bring questions to mind. We, as consumers and patients, must also ask ourselves the following questions: What separates “normal” from disorder-related behavior? What separates personality from irregularity? Is the behavior we see a result of something we can change by adjusting our lifestyle (e.g. exercising, maintaining a regular sleep schedule, eating healthier, lowering caffeine consumption, etc.) or is it the product of a genetic anomaly that would ideally be treated with medication?
Medical innovations are wonderful, but consumers must make decisions regarding what they put in their body based on their own NEED. Pharmaceuticals are not living beings that know to just go one place or only do one thing; they are chemicals designed to act on the body, many times to correct an imbalance. They act all over the body, not just in one place (though the action in one place produces the desired effect). The human body maintains a functional balance, each part affecting the whole. Putting one chemical in the brain affects one part of the balance, but because we cannot stop a chemical from circulating throughout the body, the chemical will act on other cells, causing additional effects. If we can naturally, through a lifestyle adjustment, correct an imbalance to alleviate symptoms while improving other bodily systems, it is clearly the better option because it usually does not produce negative side effects (except for less free time due to exercise, more sleep, preparing healthy food, etc.). Some problems arise from a lifestyle choice, but others are the result of things that are out of one’s control. This is where pharmaceuticals should find their niche. We have the ability to develop amazingly efficient drugs to help those in need, which is why research to help these people should continue. We must also be hesitant to attribute conditions to individual choices, but must also be careful not to immediately jump to the conclusion that pharmaceuticals are the best option. Natural remedies can alleviate symptoms and improve overall quality of life, but their maximum effect has a limit; drugs can treat the specific symptoms we need them to, but can cause side effects because of the need to get to the target area and the need to address certain symptoms. Patients acting as consumers and medical professionals acting as distributors must find a balance between the two to produce the best results for each patient.
Akt/GSK3 Pathway: Quick and Dirty Version
Let’s be honest…after a week of dissecting the article “Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptors,” I barely understand any of it. At the beginning of the week, I was staring at the article hoping some information would penetrate into my brain but all I could conjure up was the question “What does that even mean?” As the week progressed, my senior level neurochemistry class and I have been trying to wrap our cumulative 2000+ IQ brains around this dense article. At the end of this long week, I realized that the more I understood about the article, the more questions kept coming up. Although I still do not fully understand the article, I will try to sum it up for you.
Honestly, I could probably go on and tell you about every little detail in this article but I do not think that anyone wants to read it. The main purpose of the article was to explore the Akt/GSK3 signaling cascade. This cascade it initiated when dopamine binds to its D2-receptors. When dopamine is bound, a complex is formed by β-arrestin, Akt, and PP2A. The PP2A protein in the complex dephosphorylates, removing a phosphate group, Akt, resulting in an inhibited Akt. The inhibited Akt cannot phosphorylate GSK3. Therefore, GSK3 is activated and allowed to cause other cellular responses. Did you understand any of that?
Here is a quick and dirty version: Dopamine–>form complex–>inactive Akt–>active GSK3–>cellular responses
If that does not help, here is a picture!
The article focuses on this signaling cascade because of its significance in the actions of antipsychotics, psychostimulants, and antidepressants. New information about the mechanisms of action is constantly being discovered by scientists. We have learned that some antipsychotic medications previously known as dopamine receptor blockers have been discovered to activate Akt which leads to inhibition of GSK3. Is that not exciting or what? Furthermore, lithium was once thought to modulate dopamine release and blocks its binding but lithium is now known to compete with magnesium and force the complex to fall apart. This allows PP2A to phosphorylate Akt. Thus, Akt can inhibit GSK3 via phosphorylation.
I am not even sure how I am containing my excitement right now. I may not understand every piece of information that this article is throwing at me but the fact that more and more new discoveries are being made has got me jacked. It is so interesting to me that we can get a medication like lithium to treat bipolar disorder but we had no idea on how it worked so well. I think that every person, scientist or not, should be jazzed at the fact that more and more information is being revealed about this mostly unknown pathway and its connections to the brain. I hope this helped anyone to understand what in the world the Akt/GSK3 signaling cascade is. In the words of Dr. Mach’s favorite movie character Ron Burgundy, “You stay classy, San Diego.”
Wait, these drugs do what?
If I were to tell my mom I just spent a week reading and delving into an article discussing an alternative signaling pathway of the dopamine receptor involving the molecules Akt and GSK, she would probably give me a blank stare, but would smile, nod, and tell me, “That’s nice,” and then promptly change the subject to avoid discussing it further. In fact, my guess is that this is how most people would respond. I’m going to tell you a big secret: I don’t really understand it either. In fact, though there were certainly people that understood better than others, I don’t think there was a single person in our class of senior science majors that would be able to clearly explain the entire article. This brings me to an important point: in terms of science, we rarely know entirely what we are talking about. This forms the basis of scientific research—we are always in a quest to understand more.
One of the main applications of the research this article reviewed appears to be in antipsychotic medications. Many of these are pharmaceuticals which have been on the market for a long amount of time already, but we are still learning more about their mechanisms of action. This is not to say that these drugs haven’t been evaluated to ensure they meet the minimum safety requirements to be approved for use, but we are constantly learning more about how they actually work. For example, the utility of lithium in the treatment of bipolar disorder was known long before it was shown to inhibit GSK3, one of the molecules we studied this week. Previously, it was only known that lithium modulated dopamine release and blocked its binding to its receptor. Other antipsychotics which have also been used for a significant amount of time are also seeing similar discoveries. They were known to block dopamine receptors, but it was previously unknown that they also activated Akt which leads to the inhibition of GSK3. This pathway has not been explored nearly as much as others, especially the dopamine pathway that involves cAMP and PKA (two very well-known and highly-studied molecules in biochemistry).
Though it is easy to get bogged down in the technical details of these pathways, my point is this: the development and investigations upon pharmaceuticals is far more complex than most realize. Countless medications have been developed on the basis of observing the effect of some toxin in nature, and then working backwards to figure out why the toxin has that effect and how it can be manipulated and harnessed to treat disease. We often know that a treatment works, but we are not always one-hundred percent sure as to why. We become empowered, however, as we learn more and more. For instance, the pathway we studied this week appears to be at play in schizophrenia, Parkinson’s disease, and several other neuropsychiatric disorders. Though treatments have been developed for these in the past by targeting dopamine receptors, knowledge of this pathway opens up new avenues to explore in treating these conditions while potentially treating these more specifically, and hopefully developing treatments with fewer adverse side effects.
Akt/GSK3 pathway and dopamine: a target for antipsychotics
I was intrigued by one of the articles I stumbled across in the news a couple weeks ago. Neuroscience research has shown that Oreos are more addicting than cocaine. According to the neuroscientists conducting the study, eating Oreos stimulated more neurons and created greater release of dopamine than illegal substances, such as cocaine. This is just one of the example of widespread function of dopamine. I feel like most of the behaviors and discoveries that we hear about in the news are explained by dopamine signaling pathways. For example, dopamine is involved in movement, emotions, reward, pleasure, and addiction.
However, in class this week we discussed another role that dopamine plays in the brain through a unique signaling pathway. Dopamine binds to the D2 dopamine receptors (a G-protein coupled receptor) and causes its effects by increasing levels of cAMP in neurons. However, scientists are starting to learn that dopamine may also influence the Akt/GSK3 pathway as well. As this point, some people reading this blog post are thinking, “What is the world are you talking about?” and “Why the heck do I care about these things?” The basic idea here is that dopamine is acting through an additional mechanism that may provide useful targets for antipsychotics, psychostimulants, and antidepressants that are used to treat schizophrenia, bipolar, and Parkinson’s disease.
First, let’s look that the Akt/GSK3 signaling pathways under normal conditions. When dopamine binds to D2R receptors, this causes a signaling complex of proteins to form. This complex includes a magnesium ion, beta-arrestin 2, PP2A and Akt. The PP2A proteins regulates the activity of Akt when they are bound together and inactivates Akt. Like a line of dominos, PP2A controls Akt and Akt controls the activity of GSK3. When Akt is inactive, GSK3 becomes activated. Overactivation of GSK3 is thought to play a role in the pathogenesis of some neurological and neurodegenerative diseases.
So, how do pharmaceuticals target this pathway to treat conditions such as biopolar, schizophrenia or Parkinson’s disease? Lithium is one therapeutic agent that is commonly used to treat bipolar. Until recently, little was known about the mechanism of action. Research has shown that lithium affects the Akt/GSK3 pathway in two ways. First, lithium ions are similar to magnesium so they compete for a spot in the signaling complex of the Akt/GSK3 pathway. Without magnesium to stabilize the complex, Akt remains active and GSK3 remains inactive. Lithium has also been shown to directly inhibit GSK3. Antipsychotics used in schizophrenia also target this signaling pathway. For example, haloperidol increases activation Akt and inactivation GSK3. Atypical antipsychotics activate Akt or mimic its effects by directly inactivating GSK3.
Research from “Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptors” suggests a new pathway that is regulated by dopamine and is implicated in the development in many neurological diseases. Further research is still needed to answer questions about other players in the pathway. For example, what proteins or molecules does GSK3 target when it is active? Beta-catenin and neuregulins have also been shown to play important roles in the signal transduction pathways. I would still like to know more about the regulation and control of these mechanisms, as well as what other roles this pathway plays in the brain. The Akt/GSK3 pathway may prove to be an effective therapeutic target for treating neurological disorders related to dopamine.
It takes many brains to understand our own… Capstone Experience
When looking back on my experiences throughout the semester, particularly in my capstone course Neurochemistry, I think about the ability to get your point across fast. It sounds simple right? Well now imagine the topic is one of the scientific fields, and you have to sift through copious amounts of information and then crank out roughly a three minute summary of what actually should matter to a group of future scientists. It was a great experience for someone like me who loves to talk many an ear right off.
I would probably say one of my favorite discussions we had during the year was the discussion on concussions. It is a super interesting topic for someone like me, who was able to bring my love of sports, a tiny amount of biochemistry knowledge, and a “dust yourself off” mentality. Well, I had not had much experience with the science behind concussions and when I would see an NFL player get hit in the helmet prior to our classroom experience I would just enjoy the play as usual. It soon became clear that the off the field arguments about concussion treatments between the NFL players association and the NFL itself actually had a lot of people hanging in the balance. I learned that people sustaining multiple concussions actually had many long term issues associated with them.
The concussion debate actually represented everything that I would expect from a capstone course. When I thought of a capstone, I thought of the culmination of all my years here at Concordia and how I could use them to tackle a social problem using my acquired knowledge. The issue of concussions I soon learned however can’t be decided with only chemistry knowledge. Throughout the semester I came to appreciate psychology more and more. Before the class I sometimes wrote them off as the many students one floor down coasting to a 4.0 GPA, while we in the chemistry department struggle to survive. There was a large demographic of chemists in our classroom this year, but we had a couple psychology and neurosciences students that really held their own in the realm of academic discussion. I really gained an appreciation for their knowledge of the human brain as well as what chemistry was going on.
With help from our instructor, and the group of diverse students I got to know in our classroom this year I know that my grasp on things outside of my small college has been increased. I know that if I am ever to try and tackle a problem out in the real world, it will take more than just my knowledge alone, but a great supporting cast as well!
Alcohol, a Three-Headed Monster
Alcoholism is an issue in the United States that most people try to understand. In the class Neurochemistry, the chemical world often bumps heads with the psychological world. Alcohol abuse and ethanol’s effects on the brain were a great place to have that discussion again. It should be added that there are large influences from society as well.
Being twenty-one years old has its advantages in a college area like Fargo-Moorhead, you can legally drink out at the bars and take advantage of the specials that the area has on alcohol that are almost unmatched anywhere else. Think to yourself; is there a night of the week that there isn’t a drink special somewhere in FM? It is so available and widely accepted especially at the college age that its consumption around the area is common. However, leaving society’s role in alcohol consumption, the psychological role in alcohol consumption, addiction is the primary reason for the problem known as Alcoholism.
Alcoholism or being addicted to alcohol on a psychological level is a problem that can be seen in many different age groups, genders, and ethnicities. What is the difference between being chemically addicted and psychologically addicted?
Well it was learned that in people who have alcoholism, there is a strong amount of activity in the pleasure center of the brain. This was seen using PET scans of alcoholics verses the scans of their non-alcoholic counterparts. More changes in the brain cause by alcohol addiction are that it can alter mood even when sober. People who were addicted to alcohol actually showed greater responses to negative stimuli than people lacking alcohol addicting. This might help explain why most alcoholics turn to a strong drink on a bad day. It helps their brain try and equalize their reaction to negative stimuli. It was shown that through the addition of alcohol many of the alcoholics had a lessened the response due to negative stimuli.
People usually develop a chemical addiction to alcohol along with their psychological addiction; this is part of the reason that it is so hard to rid someone of their alcohol problems. It effects their body giving them sickening withdrawal symptoms as well makes them lose part of their psychological mechanism for dealing with stress or other negative stimuli.
So whether the reason is social, chemical, psychological, or some combination of all three, alcoholism is a very tricky addiction to treat even with today’s medicine. It some cases it requires a lot of help from doctors, and family alike.
Getting Knocked Around by Concussions
“Just let them play the game!” I often find myself yelling this at the television every Saturday and Sunday. My weekends often are ritualistic in that I enjoy a nice rough game of football; whether it is collegiate or professional. In recent years however I have noticed quite a bit more laundry (penalties) on the field, because the NCAA and the NFL are really trying to limit injuries such as the ones we discussed in class. The biggest injury in football that applies to neurochemistry would have to be concussions.
Do not be fooled by the habit in the NFL of a player who has “concussion-like” symptoms only being out of playing for about a week. It was discussed that the problems cause by concussions are very real, the glucose metabolism of an individual affected with a concussion drops below normal levels from minutes after the collision and can last up to weeks after the collision. This causes immediate damage to the parts of the brain such as focus and motor skills. It is even more dangerous for a person who has already had a concussion to continue playing, because they risk having another concussion. It has become an issue among NFL retirees who dealt with multiple concussions during their careers and now have many health problems because of it.
The scarier problem is that the effects of concussions are greater on younger players. The brain continues to develop up until the mid to late twenties. This means collegiate athletes who try to mimic their NFL counterparts by only staying out for a week or two are actually putting serious risk to their future mental health. Their developing brains, whether they admit it or not, are more seriously affected by trauma than an older player.
Another interesting question is: “Why is there not a universal testing system?” Well in class it was learned that there actually is a very successful test out there that has been adopted by several major sports organizations; it is called the ImPACT test. It is a computer based system that deals with “cognitive efficiency.” The patient submits a baseline at the beginning of the season and that is a stored scored for memory, reaction time, and visual reaction. The ImPACT test, while used by the NFL, MLB, and NHL, has only been mandated by the NHL.
So concluding what to take from the neurochemistry on concussions: it affects most people differently depending on the stage of brain development, it is a large problem for most contact sports, there is a system out there to help diagnose, but just because it is available does not mean it is implemented.
I am not trying to scare people away from letting their children play sports like football, but I hope that we just pay extra attention to what is happening with their mental health as well as their physical health when we put them out on the field. They represent the minds of the future and we don’t want them being knocked around too much.
Losing Control of the MAPK during Finals Week!
In the spirit of finals week, I think about a discussion on the MAPK pathway in my neurochemistry course, and the first thing that comes to mind is not a particular enzyme or disorder, but instead I think about my greatest fear. Could it be a final exam? Could it be not getting that particular job after graduation? No, my greatest fear, which is commonly shared by many people, is losing my sense of control. It is this idea of “losing control” which then builds into the things that can go wrong along the MAPK pathway. Imagine not being able to remember any of your loved ones, or not being able to control your body because you have involuntary movements. Diseases responsible for these types of feelings, Alzheimer’s, Parkinson’s, ALS (Lou Gerhig’s Disease, all can result from abnormalities and disregulation of the MAPK pathway.
What can cause disregulation of this pathway? Oxidative stress; it is something that seems to come up on a weekly basis in our classroom discussions. Free radicals present inside the bodies that are left unchecked by defense/clean up mechanisms can cause a lot of damage to a variety of different cellular processes. It is a very difficult task to limit the amount of oxidative stress on the human body, and specifically in the MAPK pathway.
The MAPK pathway is comprised of countless intricate proteins, receptors, and other subunits that can apply to any number of processes within the cell. In order for researchers to try and tinker or change certain parts of the pathway to protect us from diseases caused by oxidative stress, they run the risk of negatively affecting other mechanisms which are dependent on the products of the MAPK pathway.
So even after science has uncovered linkages between the MAPK pathway and these serious illnesses there is little that can be altered now as far as cellular mechanisms. The complexity of the human brain strikes again! However, I should not fool myself or anyone else into thinking that a defect in the MAPK pathway of the brain is the only way to get Alzheimer’s, because as we learned earlier in the semester there also may be a link between Alzheimer’s and insulin resistance. So for now all one can do are the little things; just like during finals week. Little things like eating healthier once in a while and adding some anti-oxidants into my diet may prove to go a long way. So would studying for that final exam.
Concordia's Capstone Experience
I took Neurochemistry this semester in order to fulfill my capstone course requirement for my major. What it means to take a capstone course at Concordia is that we take a special class which is suppose to examine an important subject in the world using the skills which we have acquired over our years at Concordia and to find out whether the qualities that Concordia’s mission statement espouses have been instilled within us. These qualities are a love of learning; foundational skills and transferable intellectual capacities; an understanding of disciplinary, interdisciplinary, and intercultural perspectives and their connections; an examined cultural, ethical, physical, and spiritual self-understanding; and responsible participation in the world. Thinking back on my experience in this class it I can say that I was able to use these qualities within myself for this class.
During the first quarter of this school year we learned about basic neurotransmitters and receptors, which laid the groundwork for our understanding of the articles that were to follow in the second quarter. In each article we read we were asked to identify subjects that we didn’t understand and present to the class on what we discovered in our research of each of the topics. We then had a discussion on the last day of each week, led by a pair of students, where we discussed the implications of the research and what it meant for society. This time was also a time to share personal knowledge of the issues that were being brought up. Testimonials about friends and family who suffer from the disorders being discussed in the paper. We also talked about what we were taught in our other classes about the disorder.
Looking back I think that as a class we had absorbed the true lessons that we had been taught over our time at Concordia. We had been taught more about how to approach a problem rather than what the answer to these problems were, which I think is a wise choice. The issues that we discussed in class were problems that would require more than a few bills passed in Congress, or a few new prescription medications on the market to solve. The problems that we discussed more often than not ended up being chalked up as a problem that was too difficult to solve in the hour and ten minutes that we had for discussion and we learned from our time in this class that this was okay as a lot of the papers that we read said that a lot more research would be needed to understand the numerous issues the problem that the authors were focusing on. I think that one thing for sure we could say as a class is that our time in Neurochemistry taught us that one scientific article isn’t going to put all of our questions to rest. Rather the search for answers is a long and exhausting, but at the same time exhilarating process. I think that if more people took a course like ours they would stop being so argumentative and really start discussing the issues that we face because the way forward is hard enough without us pulling each other into a fight over trifling details.