Novel Blockade of Protein Kinase A-Mediated Phosphorylation of AMPA Receptors

Vanhoose, Amanda M.; Clements, Julie; Winder, Danny G.

doi:10.1523/jneurosci.3572-05.2006

Cited by 22 publications

(17 citation statements)

References 36 publications

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“…Consistent with the notion that AMPARs are an important downstream target of b-AR signaling at synapses, GluA1 subunits are readily phosphorylated at serine 845 following b-AR activation (Vanhoose and Winder 2003;Vanhoose et al 2006;Tenorio et al 2010;Moody et al 2011;Gray et al 2014). Indeed, through protein interactions mediated by the scaffolding protein PSD-95 and transmembrane AMPAR regulatory proteins (TARPs), GluA1 subunit-containing AMPARs form a complex with b2-adrenergic receptors ( Fig.…”

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-supporting

confidence: 62%

“…Assuming that synapses contain 25 GluA1/GluA2 hetero-tetrameric receptors (Nusser et al 1998;Sheng and Hoogenraad 2007), and thus 50 GluA1 subunits, the low levels of GluA1 phosphorylation at serine 845 found by Hosokawa et al (2015) indicate that, on average, an AMPAR phosphorylated at S845 is found in only 1 out of every 100 synapses. Although b-AR activation can induce a two-to fourfold increase in GluA1 serine 845 phosphorylation (for examples, see Vanhoose and Winder 2003;Vanhoose et al 2006;Tenorio et al 2010;Moody et al 2011;Gray et al 2014), such low basal levels of phosphorylation suggest that even following b-AR activation only 0.04%-0.08% of all GluA1 subunits will be phosphorylated at serine 845. Importantly, although the vanishingly low levels of basal GluA1 phosphorylation have raised doubts about the role of AMPAR phosphorylation in synaptic plasticity, an earlier study using different approaches found that basal levels of GluA1 serine 845 phosphorylation are much higher (15% or more) (Oh et al 2006).…”

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 99%

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β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

et al. 2015

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Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the mammalian brain is norepinephrine (NE), which regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express b-adrenergic receptors, which are known to play important roles in gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in the brain. In this review, we highlight the contributions of noradrenergic signaling in general and b-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and b-adrenergic receptors in altering the efficacies of specific signaling molecules such as NMDA and AMPA receptors, protein phosphatases, and translation initiation factors. Also, the roles of b-adrenergic receptors in regulating synaptic "tagging" and "capture" of LTP within synaptic networks of the hippocampus are reviewed. Understanding the molecular and cellular bases of noradrenergic signaling will enrich our grasp of how the brain makes new, enduring memories, and may shed light on credible strategies for improving mental health through treatment of specific disorders linked to perturbed memory processing and dysfunctional noradrenergic synaptic transmission.Synaptic plasticity is a fundamental property of nervous system function. A neuron's ability to alter the strength of its synaptic connections is thought to be the foundation for multiple processes, including learning and memory. Synaptic plasticity is not a single, unitary cellular process, but rather an extremely diverse phenomenon that encompasses many forms and functions. Synapses are dynamic by nature, and only through elucidation of the mechanisms that govern their organization and reorganization can we hope to fully understand how the brain processes and stores information.Acting as potent regulatory agents, neuromodulatory transmitters can significantly alter the properties of neurons at cellular and network levels. Specifically, the modulatory role of the noradrenergic system has been extensively characterized, in part because of the system's anatomically ubiquitous connections. Noradrenergic fibers originate mainly in the locus coeruleus (LC) and project widely throughout the forebrain, with dense innervation of the hippocampus, amygdala, and thalamus (Sara 2009). These connections, especially within the hippocampus, strongly modulate synaptic strength and neural network physiology, which lead to significant alterations in learning, memory, attention, and perception. Noradrenergic receptor signal...

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Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-supporting

confidence: 62%

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 99%

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

et al. 2015

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“…NMDA treatment causes fast and reversible dephosphorylation of GluR1S845 (9,13,14), and PKA activation inhibits NMDA-induced AMPA receptor internalization ( Fig. 1 E and F), suggesting that dephosphorylation at GluR1S845 might be crucial in initiating NMDA-induced AMPA receptor endocytosis.…”

Section: Transient Dephosphorylation Of Glur1s845 Associates With Ampamentioning

confidence: 95%

Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit

Man

Sekine‐Aizawa

Huganir

2007

Proc. Natl. Acad. Sci. U.S.A.

287

291

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␣-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors mediate the majority of excitatory synaptic transmission in the brain. Recent studies have shown that activation of PKA regulates the membrane trafficking of the AMPA receptor Glu receptor 1 (GluR1) subunit, but the role of direct phosphorylation of GluR1 in regulating receptor redistribution is not clear. Here we show that phosphorylation of the GluR1 subunit on serine 845 by PKA is required for PKA-induced increases in AMPA receptor cell-surface expression because it promotes receptor insertion and decreases receptor endocytosis. Furthermore, dephosphorylation of GluR1 serine 845 triggers NMDA-induced AMPA receptor internalization. These findings strongly suggest that dynamic changes in direct phosphorylation of GluR1 by PKA are crucial in the modulation of AMPA receptor trafficking and synaptic plasticity.glutamate receptors ͉ long-term potentiation ͉ synaptic plasticity A MPA (␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, which are responsible for the majority of excitatory synaptic transmissions in the mammalian central nervous system, undergo constant trafficking between the plasma membrane and cytosolic compartments. Alterations of these dynamic processes will redistribute AMPA receptors in neurons and might underlie changes in synaptic strength, such as long-term potentiation and long-term depression (1-5).AMPA receptor trafficking is regulated by a variety of mechanisms (1-5). Activation of glutamatergic receptors, including NMDA receptors, AMPA receptors, and metabotropic Glu receptors (mGluR), triggers rapid AMPA receptor internalization (4), whereas selective activation of synaptic NMDA receptors facilitates AMPA receptor surface insertion (6, 23). Interactions of AMPA receptors with multiple proteins such as PICK1, NSF, and stargazin play a key role in AMPA receptor dynamics and its synaptic accumulation (4, 5).The intracellular signaling pathways leading to AMPA receptor relocation are being actively examined and are still controversial. The involvement of different kinases and phosphatases in protein redistribution suggests that protein phosphorylation is a major cellular mechanism in regulating intracellular trafficking (7). AMPA receptors are members of a substrate of protein kinases that includes PKA, PKC, and Ca 2ϩ /calmodulin-dependent PK II (1). Phosphorylation of Glu receptor 1) (GluR1) subunits is closely correlated with AMPA receptor redistribution and expression of both long-term potentiation and long-term depression, indicating that PKA might regulate AMPA receptor trafficking via direct phosphorylation of GluR1 subunits (1,8,9). However, the specific role of GluR1 phosphorylation has not been clearly defined. Here we report that PKA phosphorylation of GluR1 at serine 845 (GluR1S845) increases AMPA receptor cell-surface expression as the result of a combination of increased receptor insertion and decreased internalization and that a dynamic dephosphorylation of this site is critical in NMDA-dependen...

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“…Stimulation of α7 nicotinic acetylcholine receptors upregulates ERK1 / 2 phosphorylation (22). Furthermore, NMDA-receptor stimulation blocks phosphorylation of AMPA GluR1 at PKA phosphorylation site (23), and elevates phospho-ERK1/ 2 levels in cooperation with mGlu5 through the PSD-95 / Homer1b / c pathway in neurons (24). Here we showed that anionotropic GABA C -receptor stimulation up-regulates PKA activity and that this signaling is mediated by a neuronal AKAP, AKAP220.…”

Section: Discussionmentioning

confidence: 66%

GABAC-Receptor Stimulation Activates cAMP-Dependent Protein Kinase via A-Kinase Anchoring Protein 220

et al. 2008

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Abstract. In our previous study, anti-apoptotic effects of GABA C -receptor stimulation was suppressed by inhibitors of cAMP-dependent protein kinase (PKA), implying GABA C receptormediated PKA activation. The present study showed that GABA C -receptor stimulation with its agonist, cis-4-aminocrotonic acid (CACA), protected cultured hippocampal neurons from amyloid β 25 -35 (Aβ25 -35) peptide-enhanced glutamate neurotoxicity. This protective effect of CACA was blocked by PKA inhibitors, KT 5720 and H-89, as well as a specific GABA Creceptor antagonist, (1,2,5,6-tetrahydropyridine-4-yl) methylphosphinic acid (TPMPA). To test the possibility of GABA C receptor-mediated PKA activation, association of GABA C receptor with A-kinase anchoring proteins (AKAPs) and effect of an AKAP antisense oligonucleotide on the PKA activation were examined in primary cultured rat hippocampal neurons. Stimulation of the cells with CACA-activated PKA was assessed by the phosphorylated PKA substrate (135 kDa) level. Specific antibodies raised against GABA C -receptor ρ subunits precipitated each ρ subunit, AKAP220, and PKA regulatory and catalytic subunits from rat brain lysates, suggesting that ρ is associated with the AKAP220/ PKA complex. Furthermore, antisense oligonucleotide of AKAP220 suppressed such GABA C stimulation-induced PKA activation, suggesting that GABA C -receptor stimulation activates PKA via AKAP220.

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Novel Blockade of Protein Kinase A-Mediated Phosphorylation of AMPA Receptors

Cited by 22 publications

References 36 publications

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit

GABAC-Receptor Stimulation Activates cAMP-Dependent Protein Kinase via A-Kinase Anchoring Protein 220

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