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.
Akt/GSK3 pathway and dopamine: a target for antipsychotics
