Over the past week in my neurochemistry class, we discussed and learned more about an important pathway in the brain. The pathway I am referring to is called the Akt/GSK3 pathway. In order to learn more about this pathway, we discussed the article, “Beyond cAMP: The Regulation of Akt and GSK3 by Dopamine Receptors.” Even after spending a week of learning about this topic, I still have many questions that have been unanswered. On the other hand, this past week has been very beneficial and has significantly advanced my understanding of this complex topic. The Akt/GSK3 pathway has implications in the actions of antipsychotic, psychostimulant, and antidepressant medications. It is also involved in schizophrenia, bipolar disorder, so it is important to understand the basics of this pathway.
The article begins by summarizing the mechanism of the Akt/GSK3 signaling cascade. Research has shown that dopamine may play a role in the regulation of Akt and GSK3 signaling. The D2R receptor is directly involved in this pathway and its activation stimulates the formation of an important signaling complex. This signaling complex is composed of three molecules: beta-arrestin 2, PP2A, and Akt. The formation of this complex results in increased inactivation of Akt. An important discovery by researchers is that lithium disrupts the formation of this complex and inhibits the activity of GSK3. Lithium is able to disrupt the complex by directly preventing the interaction of Akt and beta-arrestin 2. Inhibiting GSK3 is the mechanism of action that many antipsychotic medications utilize.
Here is a diagram of the Akt/GSK3 pathway, which will hopefully make the pathway a little clearer and easier to follow.
In addition to having implications in antipsychotic medications, the Akt/GSK3 signaling pathway plays a role in neurodegenerative diseases, such as Parkinson’s disease. Currently, it is unclear what the mechanism is behind the role that the Akt/GSK3 pathway has in Parkinson’s disease, but researchers have discovered two neurotoxins that play a role in this disease by studying model rats. Further research on the mechanism of Parkinson’s disease will hopefully lead to an effective way to prevent this disease.
Like I mentioned earlier, the Akt/GSK3 signaling pathways plays a role in the action of antipsychotics. Several antipsychotics have been shown to be able to activate Akt and inhibit GSK3. In my opinion, it is exciting that researchers are constantly discovering different ways to produce effective medications that are useful for various different diseases. The Akt pathway is only one pathway that is utilized in the production of medications. It will be important for researchers to continually produce medications, and it is exciting that researchers are working daily to produce new effective and efficient medications.
Over the past week, it has been very interesting to learn about this important signaling pathway in the brain and see how it can be utilized in the production of numerous medications. Discussing the article has made me aware of the fact that signaling pathways in the brain are very complex and can be difficult to completely understand.
Nuts and Bolts of the Akt/GSK3 Pathway
