It is quite remarkable that the basis for the function and existence of even the most complex organisms lies at the cellular and molecular level, most of which to this day cannot be directly observed. The coordination of intra-cellular and inter-cellular events by cell signaling is essential as it determines what occurs at the functional level of the organism. This paper will focus on the cell signaling pathway of cyclic adenosine monophosphate (cAMP) and its interaction with cAMP-dependent protein kinase A (PKA) to regulate synaptic plasticity in the brain of human beings. The malfunctioning of this pathway induced by sleep deprivation will also be discussed.
Thus far, research has concluded that the cAMP and cAMP-dependent PKA signaling pathway is an important regulator in synaptic plasticity in the hippocampus. The initiation of this pathway is caused simply by the influx of calcium ions, which are already present at the synapse and function normally in neurotransmission; this process is facilitated by an N-methyl-D-aspartate (NMDA) receptor which allows calcium ions to pass through the membrane (Waltereit & Weller, 2003). This influx is followed by the activation of adenyl cyclases, specialized proteins which synthesize cAMP (Nguyen & Woo, 2003). The stimulation of adenyl cyclases by other chemical transmitters and hormones to produce cAMP has also been suggested as an alternate mechanism. These newly synthesized cAMP molecules are known as secondary messenger molecules due to their ability to further stimulate other proteins such as cAMP-dependent PKA. In its inactive state PKA is an enzyme composed of many subunits which, upon binding to cAMP molecules, dissociate and are able to phosphorylate other proteins in the cell (Waltereit & Weller, 2003).
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In the hippocampus of normal individuals, this specific activation of PKA allows the indirect regulation of synaptic plasticity through activation of associated genes; the former is the ability of the synapse between neurons to change in strength (Waltereit & Weller, 2003). Synaptic plasticity is of great interest and importance to neuroscientists as it has been shown to be associated with learning and the formation and maintenance of memory, especially long-term memory (Eckel-Mahan, et al., 2008). A study by Bernabeau and colleagues (1997) showed that cAMP mediated regulation of plasticity was especially important in a late phase of memory consolidation, when memories are being converted into a stable form. In turn this has a significant effect on the process of learning new information, a vital function in our daily lives. However it is important to notice, that there are certain factors which can interrupt the proper function of the cAMP pathway and lead to detrimental effects on memory formation.
It is well known that sleep is essential for proper functioning, and sleep deprivation has many ill-effects on the processes which occur in the body such as the regulation of synaptic plasticity by cAMP described above. A recent study by Vecsey et al., (2009) has shown that sleep deprivation has damaging effects on cAMP signaling in the hippocampus of healthy individuals. Essentially, a deficiency in sleep results in overall decreased levels of cAMP and in turn decreased activity of the sequential events in the signaling pathway, namely the function of PKA. This effect is however indirect since sleep deprivation acts on cAMP through an intermediate element phosphodiesterase 4 (PDE4; Vecsey, et al., 2009). PDE4 is an enzyme that works by directly breaking down functional units of cAMP; in sleep deprived individuals over-expression of the PDE4 gene leads to higher concentrations of the enzyme than normal and causes exessive degradation of cAMP in the hippocampus (Vecsey, et al., 2009). Evidence of normal NMDA receptor functioning and calcium ion flow suggests that sleep deprivation indeed affects cAMP signaling and not events earlier on in the pathway (Vecsey, et al., 2009). However, events following cAMP in the signaling pathway such as activation of PKA and expression genes responsible for synaptic plasticity are affected. Ultimately, this results in decreased ability to form memories, and transfer newly learnt tasks to long-term memory (Eckel-Mahan, et al., 2008).
Gaining a complete understanding of the mechanisms involved in both the proper and incorrect functioning of cell signaling pathways is important as it allows for the development of therapies and procedures to increase efficiency of cell signaling. In order to mitigate the effects of sleep deprivation on memory, synthetic drugs could be used which stimulate adenyl cyclases to produce more cAMP to increase the ratio of cAMP to PED4 which would enhance stimulation of PKA and restore proper function of synaptic plasticity. These same effects could also be attained by a therapy involving drugs capable of directly stimulating PKA in the hippocampus. Another therapy to lessen the effects of sleep deprivation could be the use of PDE4 inhibitors or a drug to degrade PDE4 to lower levels in order to prevent cAMP breakdown by the enzyme (Vecsey, et al., 2009). Effectively, the goal of these therapies would be to assure adequate stimulation of receptors and enzymes downstream of cAMP in the signaling pathway to allow the normal expression of genes responsible for synaptic plasticity in the brain.
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The cell signaling pathway involving cAMP, cAMP-dependent PKA and other molecules is important in the regulation of synaptic plasticity, a vital mechanism in long-term memory formation. Sleep deprivation decreases the functioning of this pathway; however, the creation of therapies to restore the functioning of components downstream of cAMP may serves to minimize detrimental effects such as decreased memory consolidation. If proposed therapies where successful this would support the idea the understanding of individual cellular mechanisms is fundamental to solving other health problems and finding treatments for diseases. Cell signaling mechanisms and the molecules involved are highly interwoven and the gain in our understanding of even a few of these mechanisms can help to address questions in many other fields.
In order to address this assignment I followed the order outlines by the learning tasks, which included how the signaling pathway functions in normal individuals, how it functions when an individual is sleep deprives and finally therapies which could lessen the effects caused by the lack of sleep. Challenges I faced with this assignment where that certain articles which I though where interesting by reading the abstract, could not be opened in full text. The topics discussed on synaptic plasticity are quite new (mid 21st century) and not many articles discussed how cAMP was important in this process. In order to deal with these problems I had to work with a few articles I could find and pick out the details from all the articles to combine them in to from the large picture. I learned that the processes involved in cell signaling are very complex and there is much overlap between different mechanisms.