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.
A Reflection of My Neurochemistry Experience
The experience I had in my neurochemistry capstone incorporated more of the goals for liberal learning than any other class I have taken at Concordia. Although I am biased, as I have always had a passion for neuroscience and believe that is has so many answers to questions that are raised in today’s society, I do not doubt that my classmates would similarly agree.
Each week of class we were given a scientific literature review to read and ask questions about. The beginning of the week started with a general discussion about the paper and questions that we had about the paper. As a class, we accumulated a list of topics we did not quite understand in the paper and/or wanted to know more about. At the end of class, we divided this list amongst us so that we would each be responsible for investigating a specific topic for the following class. Then, at the next class, each of us would teach our classmates about the topic we had researched more about. This information helped us to grasp the concepts of the paper far better than we had on the first day. Finally, at the end of the week, the class divided into two large groups to discuss the paper. There were not any rules to the conversation; in fact, we often strayed from the topic of the paper (eventually finding our way back).
The topics that we covered throughout the semester ranged from concussions, to autism, Alzheimer’s disease, to marijuana use, obesity, to alcoholism. The neuroscientific literature that exists in correspondence to these topics is incredible, and immensely important to progressing forward in learning about these issues. Until we learn how the body’s most important organ (again, biased), the brain, is involved in these diseases or addictions, we cannot make advancements towards treatments, or therapies, or prevention strategies that address these national and worldly issues.
The class encouraged me to pull information from so many areas of my liberal arts education as well as my own experiences. I was inspired to use my prior education as well as my new knowledge of the topics to contribute to our fascinating discussions. Actually, this was my last class on Fridays, and I always left class with our discussion still buzzing in my head hours (or sometimes even days) later. I felt that our in-class discussions stimulated within me a sense of responsibility I had to society to address these issues, even if that was simply through spreading the word about the information I had obtained.
In my opinion, neuroscience has so many answers and can contribute to putting society on a path where we are consistently “bettering” ourselves. I view neuroscience as a way to discover treatments for neurological disease and raise community awareness about neurological disorders so that we are more accepting of others, ultimately leading to a more cohesive and tolerant country.
Autism and Xenobiotics
“Methylation and redox buffering activities are equally supported by the methionine cycle and transsulfuration during normal redox conditions. [However], during oxidative stress multiple adaptive mechanisms shift the flux of sulfur resources toward GSH synthesis, including reduced activity of methionine synthase, increased activity of cystathionine-b-synthase (CBS) and decreased activity of cysteine dioxygenase (CDO). Lower methionine synthase activity reduces methylation, including dopamine-stimulated phospholipid methylation and its role in attention.”
For some readers, this paragraph might be slightly overwhelming. However, the phrases that are most important to pay attention to for the rest of this blog are italicized; normal redox conditions, oxidative stress, reduces methylation, role in attention. What do these phrases have in common? They are all important pieces in the story of autism.
Autism is a developmental disorder that affects the brain’s normal development of social and communication skills. The exact number of children with autism is unknown, but the number of diagnoses seems to be increasing. However, it is also unknown whether this is because the disorder is becoming more prevalent in the population or because there is an increased ability to diagnose the disorder.
There is little known about what causes autism, but scientists speculate that xenobiotics, or chemicals found in the body that are not normally produced by it, play a role in the development of the disorder. Researchers speculate that environmental insults (chemicals) promote oxidative stress and reduce methylation that leads to developmental delays and attention deficits as well as a lack of synchronization of neurons that is characteristic in autism.
This raises a concern for the chemicals that we encounter throughout our daily life, especially when these chemicals have such adverse effects on our bodies. It makes you wonder what other diseases these chemicals can induce in our bodies. Out of my own curiosity, I did the inevitable, and Googled it. What I found was slightly disheartening. The Agency for Toxic Substances and Disease Registry divides the bodies systems into categories and lists possible contaminants that might affect that particular system and where these contaminants might be found. For example, lead had negative effects on the renal system and can be found in old paint and outdate plumbing and nickel may adversely affect the skin and can be found in cement. The list was already quite extensive and it did not even include all the chemicals that we can be exposed to in our lifetime.
I sometimes wonder if society is so concerned with making life “easier” and more “efficient” that we forget that those things that might make life easier or more efficient for us also contain contaminants, contaminants that can harm our families and us. Or, for example, induce a disorder in children that negatively affects their social development and attention abilities.
If further research accumulates evidence pointing to certain chemicals that induce autism in children, will efforts be taken to take these chemicals off of the market? Due to the economics, I sometimes wonder if the necessary steps would be taken to do so, but ethically, it must be done.