Colocalization of Protein Kinase A with Adenylyl Cyclase Enhances Protein Kinase A Activity during Induction of Long-Lasting Long-Term-Potentiation

Abstract

The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring.

Transiently Increasing cAMP Levels Selectively in Hippocampal Excitatory Neurons during Sleep Deprivation Prevents Memory Deficits Caused by Sleep Loss

“…Because long-term memory formation critically depends on CREB-mediated gene transcription (Vecsey et al, 2007), one potential mechanism by which transiently increasing cAMP levels in the hippocampus during the course of sleep deprivation is the restoration of CREB-mediated gene transcription. Another substrate of the cAMP-PKA signaling pathway that is important for memory and synaptic plasticity is the GluA1 subunit of the AMPA receptor (AMPAR; Roche et al, 1996;Kim et al, 2011). Because sleep loss reduces hippocampal AMPAR function (Dubiela et al, 2013), including AMPAR GluA1 phosphorylation (Hagewoud et al, 2010a;Ravassard et al, 2009), our pharmacogenetic approach to increase cAMP levels during the course of sleep deprivation may restore AMPAR function, leading to proper consolidation of object-location memories regardless of sleep deprivation.…”

“…In future work, the downstream targets of cAMP in the hippocampus that ultimately mediate the cognitive deficits associated with sleep loss will be addressed. Because the cAMP signaling pathway is differentially regulated during wakefulness and sleep (Luo et al, 2013) and is negatively impacted by sleep loss (Vecsey et al, 2009), in future studies it will also be of importance to define whether different mechanisms are involved in sleep-related as opposed to wakerelated memory consolidation.…”

“…We found that 5 h of sleep deprivation attenuates hippocampal cAMP levels as a result of increased activity and expression of the cAMP-degrading phosphodiesterase 4 (PDE4) family (Vecsey et al, 2009), and cAMP signaling increases during sleep (Luo et al, 2013). Systemic injections with the nonspecific PDE4 inhibitor rolipram made memory consolidation resistant to sleep loss (Vecsey et al, 2009), indicating that hampered cAMP signaling contributes to the memory deficits associated with sleep deprivation.…”

Compartmentalization of Distinct cAMP Signaling Pathways in Mammalian Sperm

“…In mammalian sperm, cAMP has been reported to be involved in the regulation of several capacitation-associated processes such as motility hyperactivation (5), hyperpolarization of the sperm plasma membrane (51,52), and the increase in protein tyrosine phosphorylation (45). Because of its relevance for cell processes, cAMP levels are tightly regulated both temporally and spatially by different types of adenylyl cyclases and cAMP phosphodiesterases (53)(54)(55). Two families of adenylyl cyclases are responsible for cAMP synthesis in animals as follows: the tmACs (Adcy1-9) and the FIGURE 2.…”

Genealogical correspondence of a forebrain centre implies an executive brain in the protostome–deuterostome bilaterian ancestor

“…For example, null mutations of the gene encoding Drosophila protein kinase A catalytic subunit (DC0), an orthologue of mammalian protein kinase A catalytic subunit alpha (PKA-Ca), result in poor performance of olfactory memory tasks [13]. Protein kinase A is also necessary for the formation of long-term memory in the vertebrate hippocampus and in the Drosophila mushroom bodies [13,14,54,55]. Numerous other orthologous genes have been identified in hippocampus and mushroom bodies that are required for the same functions in each (table 1).…”