cAMP-dependent protein kinase A and phosphodiesterases in relation to maintaining synaptic plasticity vital to learning and memory. Sleep-deprived individuals, students for example, sometimes adopt a vegetative demeanour: for one thing, the ability to learn is minimal to nonexistent. A possible explanation relates the cell signalling molecule cyclic adenosine monophosphate (cAMP) levels to a decrease in cognitive ability. As the tetrameric holoenzyme PKA is exclusively activated by cAMP, but cAMP synthesis is regulated by many different external signals, focus will be placed on the interactions between cAMP and PKA (Figure 1; Graves, Pack and Abel, 2001). Sleep deprivation (SD) negatively influencing intracellular cAMP levels and PKA activity is the putative molecular mechanism behind decreased synaptic strength. The modified synaptic transmission ability then goes on to affect neuronal long-term potentiation and consolidation of experiential learning into long-term memories. As research findings support a relationship between the effects of SD and low cAMP levels, inhibiting cAMP enzymatic degradation is a potential treatment; albeit sleep would be the best solution for the sleep-deprived if it were an option!
cAMP relays extracellular signals to intracellular processes by initiating the PKA phosphorylation cascade. cAMP production from ATP is stimulated by ligand binding to transmembrane G-protein coupled receptors or Ca2+ flow that in turn activate membrane-bound adenylyl cyclase (Nakano, Doi and Yoshimoto, 2010). The newly synthesized cAMP proceeds to allosterically activate PKA by promoting the conformational changes and eventual dissociation of the regulatory subunits from the catalytic subunits (Abel and Nguyen, 2008). The serine kinase PKA then activates proteins such as a family of enzymes known as phosphodiesterases (PDEs). Breaking the cyclic structure, PDEs are the sole regulation method moderating intracellular cAMP levels and preventing overinduction of cAMP-PKA processes (Vecsey, Baillie, Jaganath et al., 2009). Besides PDE, PKA phosphorylates many different proteins depending on the cell type (i.e. DARPP-32 in medium spiny neurons; Nakano et al., 2010). One particular grouping of proteins activated by PKA is involved with establishing synaptic strength.
PKA is involved in the learning process by promoting synaptic plasticity, a key factor in neuronal information storage. Otherwise known as synaptic potentiation, plasticity refers to the ability of the presynaptic and postsynaptic neuron to respond through neurotransmitter release and uptake. Synaptic strength has been found to be affected by a range of cellular processes including expression of plasticity proteins, and unmasking or phosphorylation of neurotransmitter receptors, all of which are attributed to active PKA (as reviewed by Nguyen and Woo, 2003). Particular changes in potentiation known as long-term potentiation (LTP) are fundamental in memory development (Abel and Nguyen, 2008). Work with Aplysia and Drosophilia indicate the establishment of LTP solely in the presence of PKA (Nguyen and Woo, 2003); but now, the caveat is discerning the molecular processes involved. cAMP response-element binding protein (CREB) is a transcription factor, that once phosphorylated, initiates transcription of genes believed to be involved with plasticity. It was found that specific inhibition of PKA in the nucleus lead to the absence of LTP alongside decreased levels of phosphor-CREB (Nguyen and Woo, 2003). Learning and memory are indirectly affected by PKA activity due to dependence of CREB on PKA phoshotransferase activity to transcribe genes involved in LTP.
In patients with SD, the cAMP/PKA system goes awry and memory is affected. During the period immediately following the time of knowledge acquisition, increased PKA levels, a rise in levels of phospho-CREB and protein synthesis occur are observed. Without these molecular events, experience-based learning (i.e. fear of electrical shock) is nonexistent (as reviewed by Graves et al., 2001). Vecsey et al. (2009) examined PDE levels in SD organisms post-“training”. Compared to controls, concentration and activity of PDE-cAMP increased; overall, the concentration of cAMP was lower after SD. Studies with a modified protocol testing for the effect of SD on memory, yielded agreeable results, suggesting sleep and PKA control the learning process by influencing CREB-related protein synthesis (Graves et al., 2001). Beyond the initially effecting synaptic plasticity via cAMP/PKA, sleep also affects synapses and memory during the consolidation or storage stage. It has been found that PKA inhibition prevents consolidation of changes in synaptic plasticity, an effect that be reversed with sleep (Aton, Seibt, Dumoulin et al., 2009). The parallel between SD and PKA-related processes provides evidence that SD impairs initial synaptic plasticity by inhibition of PKA.
As PKA and CREB activation is dependent on the presence of cAMP, inhibition of PDE-mediated degradation is a potential clinical treatment. Viewed as critical in regulating cAMP-dependent processes, PDEs are able to antagonize the potentiation of neurons (Zaccolo, 2006). PDE antagonism as a target for improving memory has been demonstrated both in vitro and in vivo (Barad, Bourtchouladze, Winder et al., 1998; Vecsey et al., 2009). This, however, is not to say that simple increase in concentration is beneficial. Outcomes are varied when comparing genetic manipulations that increase cAMP levels compared to cAMP signals (as reviewed in Abel and Nguyen, 2008). Higher basal levels have deleterious effects on memory, whereas increases in signal strength (i.e. a larger flux of cAMP from overexpression of adenylyl cyclise) have a beneficial effect similar to PDEs. PDE inhibitors reversing the effects of SD on memory and context-dependent cAMP-PKA interactions encourages investigation into the cAMP and PKA relationship. Hypersensitization of inactive PKA being activated by cAMP (through conditional mutation; Abel and Nguyen, 2008) may help increase understanding this critical step in interplay between cAMP/PKA and memory-learning processes.
The cAMP-dependent protein kinase A signalling system affects the ability of SD individual to learn and consolidate memories. Through PKA, SD is found to negatively impact synaptic plasticity in neurons because SD is capable of quenching the cAMP/PKA system via PDE. Without PKA activating the transcription factor CREB, increasing levels of proteins related to synaptic plasticity, sleep-deprived individuals will not be able to learn from their tragic flaw of sleeplessness.
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Figure 1. Multiple extracellular signals converge to activate protein kinase A through cAMP synthesis via adenylyl cyclase in neurons. Extracellular effectors such as acetylcholine (Ach), glutamate (Glu), serotonin/5-hydroxytryptamine (5-HT), calcium ions (Ca2+) and potassium ions (K+) activate adenylyl cyclase (AC). AC products cyclic adenosine monophosphate (cAMP) which activates protein kinase A (PKA). Activated PKA goes onto to effect multiple proteins, one of the major ones being the transcription factor cAMP response-element binding protein (CREB). Figure reprinted from Graves et al., 2001.
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