Effects Of Sleep Deprivation On The Camp Pathway Biology Essay


It has long been demonstrated that sleep deprivation hinders memory consolidation. However, the biomechanisms between sleep and memory are not as well understood. One can look to the molecular level and use cell signaling pathways to explain this phenomenon.

One of the sleep cycle phases, rapid eye movement (REM), is frequently associated with memory consolidation for the reasons that REM increases acetylcholine (ACh) levels, decreases neurotransmitter serotonin levels and increases levels of Ca2+ (Graves, Pack & Abel, 2001). In order to describe their influence at a molecular level, it is essential to explore the cell signaling pathway associated with memory consolidation.

Levels of cyclic adenosine monophosphate (cAMP), secondary messengers in signaling, are affected by sleep deprivation. The cAMP pathway is active in neurons and concentrated in the hippocampus region for memory consolidation (Karp, 2008). Under normal conditions, the cell produces cAMP as a response to a stimulus such as the three outlined above (Graves et al., 2001). Heighten levels of this messenger cause an activation cascade that will ultimately regulate cellular processes in the nucleus.

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The mechanisms of the cAMP pathway will be described. Signaling cells release molecules, known as first messengers, which are recognized and bound by receptor cells (Karp, 2008). These messengers include ACh, serotonin and Ca2+ (Graves et al., 2001). The signaling molecules exchange GDP to GTP, causing a conformational change in Gα of the trimeric G protein and its release from the β and γ subunits (Karp, 2008). Gα is able to bind and activate an effector. Effectors are integral membrane proteins with domains located on the inner surface of the plasma membrane, thus allowing the cell signal to move from outside to inside the cell. For the cAMP pathway, the effector is adenylyl cyclase (AC) which catalyzes the secondary messenger, cAMP, from ATP. These mechanisms create signal amplification as many secondary messengers are produced from the activation of a single effector. Furthermore, a secondary messenger activates a cascade of proteins which in turn regulate many other cellular processes.

Under sleep deprivation, levels of Ach and Ca2+ decrease and serotonin increase, resulting in lowered cAMP activity as the biochemical consequence due to the lack of REM (Figure 1, Graves et al., 2001). ACh is known to activate muscarinic acetylcholine receptors which, by coupling to the trimeric G proteins, stimulate AC and cAMP production. Additionally, heightened levels of calcium activate AC to create cAMP by moving into the cell via ligand gate ion channels known as N-methyl-D-aspartate (NMDA) receptors. Decreased levels of serotonin stimulate the formation of cAMP as the neurotransmitter is known to be negatively coupled to AC.

After its synthesis, cAMP diffuses further into the cytoplasm and binds to the allosteric sites of cAMP-dependent protein kinase (protein kinase A, PKA). PKA is an enzyme with four subunits; two regulatory and two catalytic (Karp, 2008). In its inactive form, the regulatory inhibit the catalytic subunits. However, cAMP acts as an inhibitor by binding to the allosteric site of PKA and stopping the inhibition of the regulatory subunits. This allows for substrates to be catalyzed. The cAMP-PKA complex is known as the cAMP element-binding protein (CREB) and is transported to the nucleus. CREB binds to cAMP response elements (CRE) which are DNA with the sequence TGACGTCA (Lalli & Sassone-Corsi, 1994). These specific DNA sequences are close to promotor regions and can up-regulate gene expression of particular amino acids and proteins needed for memory consolidation.

Levels of cAMP regulate gene expression by stimulation and repression. One study found that numerous genes from the cerebral cortex and the hypothalamus had different patterns of expression during wakefulness and sleep deprivation (Mackiewicz, Shockley, Romer, Galante, Zimmerman, Naidoo, Baldwin, Jensen, Churchill, Pack, 2007). A similar trend was found in the levels of transcription. Heightened levels of cAMP increases transcription of specific genes but will also decreased the transcription of others. These up-regulated genes were identified to be genes associated with cellular transportation and transcription (Mackiewicz et al., 2007). Down regulated genes were linked with metabolism. It is the inhibition of cAMP activity during sleep deprivation that suppresses essential genes and the ability for the body to restore such molecules that are needed for wakefulness and memory consolidation. By understanding the cAMP pathway and mechanisms, it is possible to develop potential therapies.

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From a molecular perspective, possible therapies resulting in heighten memory consolidation during sleep deprivation would involve raising the lowered cAMP signaling activity. It is seen that lowered cAMP levels result in repressed gene expression of the biosynthetic products needed for memory consolidation. There are many target areas for drug therapy in the cell signaling pathway. Such examples would include compounds which would enhance AC and PKA activity to further the cell signal amplification. Since cAMP molecules are destroyed by cAMP phosphodiesterase, another possible therapy would be phosphodiesterase inhibitors that prevent the enzymatic degradation of cAMP molecules (Vecsey, Baillie, Jaganath, Havekes, Daniels, Wimmer, Huang, Brown, Li, Descalzi, Kim, Chen, Shang, Shuo, Houslay, Abel, 2009).

Sleep deprivation deprives the body of REM sleep and as a result, decreases the levels of Ach and Ca2+ while increasing the levels of serotonin. The three compounds are a few of the many stimuli that activate AC to synthesis cAMP. As a secondary messenger, cAMP activates PKA to travel to the nucleus as a complex known as CREB. In the nucleus, TGACGTCA sequences of DNA are bound by CREB which allows certain genes to be up-regulated and down-regulated. The specificity of the genes transcribed dictates which essential amino acids and proteins are produced for memory consolidation. At a molecular level, sleep deprivation directly affects the cAMP cell signaling pathway which has consequences for memory consolidation. Serving as a link between sleep and memory, the cAMP pathway also offers a feasible mechanism for the creation of student zombies.

Number of words excluding references: 900


Figure 1: The effects of acetylcholine, serotonin and Ca2+ on AC and cAMP synthesis retrieved from Graves et al., 2001