The article in question is a review article that brings together research about PKC and sheds some insight on the methods and results, similar to what this blog post is attempting to accomplish. This article connects Biochemistry research to our neuroscience class by providing additional information about the research conducted by Jessica Hoffman, who we had the pleasure of listening to a talk about her research on Inhibition of AMPA receptors.
Protein Kinases add phosphate groups to proteins, which changes their activity or how they interact with other proteins. Isoforms (different versions) respond differently and require a different signal. These isoforms are important because they may have conflicting effects since they require different signals. PKC in neurons affects neurotransmitter release and synaptic plasticity, both of which contribute heavily to learning and memory. This article chooses to focus on changes in both presynaptic and postsynaptic mechanisms, like release of neurotransmitter vesicles and AMPA glutamate receptors.
PKCs can be both harmful and beneficial depending on the perspective, but do not fall into either category entirely. The article suggests that it may be possible for PKCs to be extremely beneficial if a treatment were to specifically target an isoform required. In this article, the authors link PKC activity to several factors in Alzheimer's disease, and how inhibiting/increasing activity affected the event in question. The three key factors mentioned in the articles were Amyloid-beta production, synaptic disfunction and Tau abnormalities. Synaptic disfunction may be caused by PKCs by receptor regulation, which may cause issues with plasticity that memory formation requires to properly function.
In amyloid-beta production, PKCs can affect the amyloid precursor protein by influencing the enzymes that convert the substrate to product. The article described evidence linking PKCδ to an increase in Beta secretase-1 or BACE1 expression, and amyloid-beta production. This enzyme is the rate limiting step in the reaction that form amyloid beta, as this enzyme creates the first cut on the precursor protein. While this is a good point to discuss, the article also mentions some protective effects of PKCs, with the key takeaway being that PKCs aren't uniformly harmful in this aspect of AD.
The effect PKCs have on Tau vary between isoform and phosphorylation sites, and PKCs may not be the direct cause of any abnormalities. The article mentions that PKCs may affect Tau directly, but may also have an influence by affecting other signaling mechanisms. Tau plays a big role in neuronal microtubules, and any abnormalities in phosphorylation can cause tangles or collapse of the neuron itself. As these neurons die, they release the toxic Tau and infect more parts of the brain, which leads to a chain reaction that can eventually infect entire cortical areas.
Both articles aren't exactly similar, but they do have some similarities that may be worth exploring. They both connect alcohol to memory and learning and emphasize treatment specificity. Both studies do not examine the same mechanism when it comes to alcohol, but one can connect the two by looking at synaptic plasticity.
However, for treatment specificity, there are a few more connections that can be made. The PKCs studied mentioned in this research show how a single change in a signaling pathway can have different outcomes based on the protein receiving these signals. The Hoffman study limits their exploitation of signaling pathways to a single AMPA receptor population, as organism-wide inhibition would likely interfere with normal function. The key takeaway from both of these texts is that it is very important to specify the target, the cells it resides in, and the organism itself.
Overall, these texts interested me for a few reasons. Connecting biochemistry to neuroscience applications is something I strive to do in my future, and this was a good example of how the two fields coincide with each other. I thought it was interesting to see alcohol usage's effects in multiple perspectives and experiments, which really highlights how complex the brain really is, and how much more there is to be discovered.
Singh, N.; Nandy, S.K.; Jyoti, A.; Saxena, J.; Sharma, A.; Siddiqui, A.J.; Sharma, L. Protein Kinase C (PKC) in Neurological Health: Implications for Alzheimer’s Disease and Chronic Alcohol Consumption. Brain Sci. 2024, 14, 554. https://doi.org/10.3390/brainsci14060554
Hoffman, J. L., Faccidomo, S., Saunders, B. L., Taylor, S. M., Kim, M., & Hodge, C. W. (2021). Inhibition of AMPA receptors (AMPARs) containing transmembrane AMPAR regulatory protein γ-8 with JNJ-55511118 shows preclinical efficacy in reducing chronic repetitive alcohol self-administration. Alcoholism, clinical and experimental research, 45(7), 1424–1435. https://doi.org/10.1111/acer.14639
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