The Sacrifice Of Sleep Deprivation Biology Essay


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Cyclic adenosine monophosphate (cAMP) is a secondary messenger which is integral to many biological pathways. Secondary messenger systems utilize rapidly produced, diffusible signalling molecules which then go on to activate effecter proteins (Karp, 2010). A principle protein target for cAMP is cAMP-dependant protein kinase (PKA). PKA regulates intercellular signal transduction in many biological systems through reversible phosphorylation. One such function of PKA is chemical synaptic transmission which is the foundation of synaptic plasticity. The ability of neurons synapses, or connections, to change in strength underlines the definition of this system. Man's capacity to learn, remember and perceive is shaped by synaptic plasticity. PKA is pivitol in long term memory or long term potential (LTP) of mammals. This signalling cascade is highly conserved among species (Nyugen and Woo, 2003). Intro = 1/2

PKA is composed of four regulatory subunits (RIα, RIβ, RIIα, RIIβ), each with two cAMP binding regions, as well as, three catalytic subunits (Cα, Cβ, Cγ), which are released following binding of cAMP. In the absence of cAMP, PKA remains inactive as a tetrameric holoenzyme. The cataylic units, once released, serve as phosphate binding regions. The activation of PKA assists in regulating protein synthesis. One transcription factor, activated by PKA phosphorylation, cAMP response element binding protein (CREB) modulates transcription of promoters. The proteins that are synthesised by CREB modify structures in synaptic transmission. Specifically, the physical structure of the dendritic spines changes when LTP is established. An increase in the density of dentrites is paralleled by the increase of CREB in hippocampal neurons.

A precursor for cAMP pathway is the activation of adenylate cyclase enzyme. The adenylate cyclase complex, located at the plasma membrane, is composed of three subunits: a guanine nucleotide binding protein, a hormone receptor, and a catalytic component. It is the catalytic component of the adenylate cyclase which converts ATP to cyclic adenosine monophosphate (cAMP) (Khanum and Dufau, 1986). Physiological regulation of adenylate cyclase primarily occurs via hormones interacting with receptor regions and the co-activation of guanine nucleotide binding protein. In the 1980s, a novel activator of adenylate cyclase, forskolin, was identified. Forskolin interacted with adenylate in a rapid and reversible fashion. A study conducted by Seamon and Daly (1981) demonstrated the functionality of forskolin in the absence of a guanine nucleotide binding protein. In light of this information, it is clear that forskolin plays an intimate role in cAMP signalling.

In normally functioning cells, cAMP is regulated by a number of inhibitors. These inhibitors can act to prevent the binding of specific hormones to the hormone binding receptor of adenylate cyclase, impede binding to the catalytic subunit or the guanine nucleotide receptor (Chen et al, 1980) (Reid et al, 1990) (Cassel et al, 1979). Aside from hindering their production, cAMP levels can be controlled by phosphodiesterases (PDE). These enzymes function to hydrolyse the bonds within cAMP once sufficient levels are reached. (Vecsey et al, 2009).

Sleep deprivation is a major contributor to memory and learning defects in otherwise healthy individuals. As cAMP signalling is closely associated with synaptic plasticity, a possible connection between the sleep and cAMP signalling can logically be derived. Vecsey et al confirmed the mechanistic connection between cAMP and sleep in 2009. The mouse model used by Vecsey's team utilized forskolin to initiate cAMP synthesis. It was observed that maintenance of LTP was impaired in CA1 region of the hippocampus of sleep deprived mice. Within these samples, the baseline levels of cAMP were significantly reduced. In addition, the phosphorylation of CREB was decreased in the test subjects. Without phosphorylation, CREB cannot be activated and in turn, the proteins which modify the dendritic spines will never be synthesised.

One explanation for the decrease in cAMP levels is the possible desensitization of the CA1 region cells of hippocampus to adenylate cyclase activation; however, this theory is yet to be fully substantiated by empirical evidence. The increased levels of PDE observed in mice models, acts as a supplementary explanation for the reduction of cAMP. Sleep deprivation appears to increase the activity of PDE which is the sole source of cAMP decomposition. If cAMP is being degraded, quickly following its synthesis, it will never initiate PKA which then prevents the phosphorylation of CREB (Vecsey, 2009).

For the lives of undergraduate students, understanding sleep deprivation is paramount as periods of sleep deprivation is almost always associated with late night essay cram sessions. Vecsey (2009) utilized 3-isobutyl-1-methylxanthine treatment to rescues the impairments in forskolin induced cAMP levels. This treatment is a PDE inhibitor. By preventing the activity of PDE, cAMP levels can return to a functional level. A more universally impactful use of the general understanding cAMP's role in memory and learning lays down the ground work for understanding how memory disorders, and aging effect cognitive function. When knowledge of the mechanisms affected by sleep deprivation is available, the possibility of counter measures exists. Harnessing the knowledge that the density of dendrites is proportional to LTP could be applied to counteract the forgetfulness that comes as a hallmark of aging or act as a therapy for memory disorders. Supplementing the levels of cAMP in the hippocampus can further increase man's memory potential. Since the mechanism behind Alzheimer's disease continues to elude scientists, studying methods to augment LTP could rescues countless lives.

It can be argued that man's immense capacity to learn, remember and perceive is what separates us from the animals. This ability should be nurtured and not taken for granted. Sleep deprivation is growing problem in our fast paced society. Relaying the information from papers, such as those summarized in this essay, may assist in curbing society's incessant need to sacrifice sleep to in order to deflect the ticking clock.

Personal Response:

I began my research bent on the topic of sleep deprivation and insulin production. This proved to be unsuccessful after two fruitless days of scouring papers trying to find a description of the exact mechanism of insulin production that is effected by sleep deprivation. I finally ceded to the lack of information and moved on the cAMP signalling. The research for this was extraordinarily easy relative to insulin production. I began with a top down method as I found a study that described the effect of sleep deprivation on cAMP mechanisms. I then used Wikipedia to look up key words I identified in the article: cAMP, CREM, FSK, PDE etc. This helped me centre my research as cAMP has many activators. By focusing on the forskolin activators and phosphodiesters inhibitors, I was able to create flow in the paper.

Chen, T., Rosenblatt, M., Puschett, J. (June 1980). Effects of calcium on a parathyroid hormone-sensitive adenylate cyclase inhibitor. Biochemical and Biophysical Research Communications 94(4), 1227-1232.

I needed an example of a competitive inhibitor for the hormone binding site and this covered that.

Karp, Gerald. 2010. Cell and Molecular Biology, Concepts and Experiments. Hoboken, N.J.: John Wiley & Sons, Inc. Sixth edition

Good for definition of second messengers.

Khanum, A., Dufau, M. (March 1986). Inhibitory action of forskolin on adenylate cyclase activity and cyclic AMP generation. The Journal of Biological Chemistry 25, 11456-11459.

This article supported the findings of Seamon and Daly and summarised forskolin sufficiently. Furthermore, it provided the inhibitory function in normal cells.

Nguyen, P.V., Woo, N.H. (December, 2003). Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases. Progress in Neurobiology 71(6), 401-437.

This article was amazing in outlining the connection between cAMP and memory. It was very detailed which allowed me to safely paraphrase.

Reid, I.R., Lowe, C., Cornish, J., Gray, D.H., Skinner, S.J. (1990). Adenylate cyclase blockers dissociate PTH-stimulated bone resorption from cAMP production. Endocrinology and Metabolism 258(4), 708-714.

This was an example of an inhibitor for the catalytic subunit.

Seamon, K., Daly, J. (July 1981). Activation of adenylate cyclase by the diterpene forskolin does not require the guanine nucleotide regulatory protein. The Journal of Biological Chemistry 256, 9799-9801.

This article presented a clear method for determining the relationship between forskolin and adenylate cyclase. The experimental procedure covered all the bases and didn't leave room for doubt in the researcher's conclusions.

Vecsey, C.G., Baillie, G.S., Jaganath, D., Havekes, R., Daniels, A., Wimmer, M., Huang, T., Brown, K.M., Li, X.Y., Desclazi, G., Kim., S.S., Chen, T., Shang, Y.Z. Housley, M.D., & Abel, T. (2009). Sleep deprivation impairs signaling in the hippocampus. Nature, 461(7267), 1122-1125.

This article outlined how sleep deprivation effects specific cAMP pathways wonderfully.

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