If I’ve learned anything while at Concordia, it’s that there’s always something else I can learn. This week in neurochemistry only helped to make this more evident. After the first read-through of the article “Beyond cAMP: the regulation of Akt and GSK3 by dopamine receptors,” it really felt like I haven’t learned anything. However, after hashing it all out in class, we were able to piece together a very promising and intriguing protein signaling cascade. So why should we care about this pathway? Whether we realize it or not, every process that occurs in our body is ultimately the result of chemical reactions. When these reactions start to go wrong and processes start to fail we wind up in a pathological state.
So how does this all relate to Akt, GSK3, and dopamine? Dopamine is a chemical that acts within the brain and the rest of the body. Referred to as a neurotransmitter, dopamine is used to send signals between neurons. Dopamine is able to signal the occurrence of events in the body by binding to one of five dopamine receptors. When dopamine binds to the D2 receptor a signaling event involving Akt and GSK3 is initiated. Here’s how it works: dopamine binds the D2 receptor, a complex of β-arrestin, Akt and PP2A is formed, PP2A takes a phosphate group off of Akt (causing its inhibition), and GSK3 is activated. If you’re confused, that’s okay. Basically all you need to remember is that the binding of dopamine to D2 receptors causes the activation of GSK3.
Right about now, you’re probably thinking “Cool, and I care why?” Researchers have been studying this pathway, specifically GSK3 and the molecules it acts on after it is activated. It is now believed that a variety of disorders are associated with the Akt/GSK3 pathway. These conditions include: depression, schizophrenia, bipolar disorder, Parkinson’s Disease, and addiction. In addition, various cell processes are now believed to be implicated with this pathway. Studying pathways such as the Akt/GSK3 pathway offers a way to learn more about these conditions. In addition, a better understanding of the mechanism by which these pathologies present could bring to light novel treatments.
This pathway exemplifies the idea that there is always something else to learn. Although researchers have been studying these conditions for some time, they are just now beginning to discover a mechanism by which they MIGHT work. From a scientist’s perspective, the most exciting thing about this is not what they’ve already discovered about the Akt/GSK3, but the fact that it is just scratching the surface. There is undoubtedly a variety of targets that are downstream from the GSK3 protein that are involved in countless mechanisms. Even more, this is just one pathway; the body is filled with signaling pathways that make you function! While the discovery of the Akt/GSK3 pathway and its targets is exciting, it’s even more exciting to think of where it may take us.
I thought that was illegal….
When many people hear the acronym THC, they think of the illegal (in most places) drug marijuana. But the article Endogenous cannabinoids revisited: A biochemistry perspective sheds light on how this psychoactive chemical has led to research into naturally occurring cannabinoids in the human body and how their regulation can be beneficial. The system of receptors in the human brain that responds to THC and other cannabinoids is the endocannabinoid system. This system was discovered after researchers took a look at the way in which THC worked in the brain. As a result, many molecules were made to resemble THC and were used to help understand its psychotropic properties.
What I personally find most interesting from this article is the fact that researchers found a system of receptors, occurring naturally, in the brain that works by binding molecules very similar to THC. It makes one think, if there is a natural purpose for molecules similar to THC, is THC really all that bad for a human? The article goes on to describe pathways and signaling of two molecules very similar in structure to THC, AEA and 2-AG. These two molecules are present in human brains and are used for pain relief, motor control, stimulation of appetite, and inhibition of cell growth. The article goes on to talk about similarities between both the structures and effects of these naturally occurring compounds, AEA and 2-AG, and THC, the dangerous, illegal active ingredient in marijuana.
When looking at how similar these substances are, it wouldn’t be extraordinary to question why marijuana is not used more frequently for medical purposes. Since it shares many characteristics of naturally occurring molecules, the side effects of THC and marijuana on the body seem minimal when compared to other prescription drugs. Many drugs prescribed on a daily basis come with a long list of cautions warning people about possible negative side effects, but the review article we read for the week explained how there seem to be few consequences of consuming marijuana for pain relief or to help regulate appetite.
People opposed to the use of medical marijuana may combat the argument of its therapeutic effects with its addictive nature. The informed person knows that many prescription medications have a high risk of causing addiction. Many people become addicted to sleep aids and pain killers that were legitimately prescribed to them to deal with some sort of condition. But yet there is much less of a stigma of proper use of these drugs than there is for legitimate use of marijuana for medical purposes. It seems to me that by the general public insisting that marijuana is not suitable for actual medical use, we are missing out on a potent source of natural pain alleviation.
In my opinion, with all of the information this paper was able to provide about the naturally occurring endocannabiniod family of receptors, it would be more useful to figure out a way in which we can harvest the rich medicinal use of THC from marijuana (or other forms of THC) in a responsible manner. Worrying about the minimal side effects and possibility of addiction seem to be clouding the vision of many people who could be working towards more safe, natural drugs that can do the same things synthetic ones can do. So yes, you are correct in thinking marijuana is illegal in many of the states in the US, but according to the research presented in this week’s article, it would also be correct and easy to ask why it isn’t used more in modern medicine.
A New Look at Medical Marijuana
Last week, we tackled the topic of the endocannabinoid (EC) system and the implications of marijuana for medicinal purposes. Often only the recreational uses are acknowledged. However, the article “Endogenous cannabinoids revisited: A biochemistry perspective” describes the signal transduction pathways of ECs and physiological effects.
Researchers first realized that ECs existed when they discovered that Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, was able to bind to two types of receptors. CB1 receptors are found in the brain, immune system, vessel walls, intestine, liver, peripheral nervous system, and reproductive tissues and CB2 receptors are found in the immune system. This led the researchers to believe that there were molecules in the body that were structurally similar to THC. Further research showed that there are two main endocannabinoids produced in the body: anandamide or arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). AEA and 2-AG influence analgesia, motor response, inflammatory response, feeding behavior and other biological processes. More recently, it has been discovered that endocannabinoids have an effect on cell survival signaling. Cannabinoid signaling may induce apoptosis (cell death) through a number of pathways. This may prove useful in therapeutic treatments because it has been shown to be linked with anti-inflammatory, anti-proliferative and cytoprotective effects.
Now how does this all relate to medicinal marijuana use? Well, THC is similar in structure to 2-AG and AEA so it has may similar effects to these molecules. One of the main reasons that medical marijuana is used is to treat chronic pain in diseases such as cancer, diabetes, spinal cord injuries, and multiple sclerosis (MS). THC has also been shown to affect feeding behavior. Cannabis is being used to treat nausea associated with chemotherapy and increase food consumption in anorexic patients. CB1 and CB2 receptors are found in the immune system, which has led to the use of cannabinoids to treat MS, rheumatoid arthritis and inflammatory bowel disease. Researchers are looking into the molecule known as cannabidiol, another molecule in cannabis, because it has been shown to produce fewer psychoactive effects.
With new knowledge comes the responsibility to use it ethically. How should society approach the use of medical marijuana? Should it be legalized or should we approach the use of medical marijuana with caution? It is important to keep in mind that currently marijuana is considered by Drug Enforcement Administration (DEA) to be a Schedule I drug. According to this classification, schedule I drugs have no medical uses and a high potential for abuse. Research showing that cannabinoids are effective in treating symptoms associated with autoimmune diseases, neurodegenerative disorders, chronic pain, and cancer may be a reason to reconsider the current classification. Also, cost versus benefit must be weighed when considering therapy options. Many of the current medications used to treat diseases have harsh side effects. Much of the current research points to the positive effects of cannabinoids and few negative side effects. Further research will need to be done to fully understand the effects of cannabis. With proper regulation, it appears that medical marijuana may provide beneficial effects in a number of diseases.
What's Not to Love?
The article this week revolved around a topic that has been debated in many political and medicinal, as well as ethical, discussions. After reading and discussing this article, and doing some questionable Google searches, my understanding of cannabinoids and the pathways affected by them has increased drastically. Learning the basics of what becomes influenced was interesting, but what really captivated my attention was the side-effects cannabinoids produced, or rather lack thereof. Of course there are precautions that need to be taken when putting anything into our body. However, it amazes me the amount of stuff we can put into our bodies that are considered “medicine,” yet they have so many awful side-effects. It blows my mind that addictive pain killers are prescribed on the daily, but this natural pain killer is illegal almost everywhere in the United States. It’s fascinating how many medicines have been rushed to the market with only the minimal amount of research done for it to become a drug, but cannabinoid is still illegal despite all of the studies done inside, and outside, the lab where it has been proved to be beneficial to people’s ailments.
I’m not advocating for everyone to go and get baked on the daily, but I don’t see the problem with people being able to access a natural therapy for pain, eating disorders, etc. We have become a society that is obsessed with “fixing” everything, and if we have found a fix for all sorts of psychological problems, why not implement it? It’s not uncommon to have cabinets full of bottles we barely know what they do to our brain, yet this drug we know the pathway for and a lot of its positive side-effects for shouldn’t be among them. There must be a believable argument for why cannabinoids should not be allowed for medicinal uses, but I have yet to find it.
What Are We Really Affecting?
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!