Control of GluR1 AMPA Receptor Function by cAMP-Dependent Protein Kinase

Banke, Tue G.; Bowie, Derek; Lee, H.-K.; Huganir, Richard L.; Schousboe, A.; Traynelis, Stephen F.

doi:10.1523/jneurosci.20-01-00089.2000

Cited by 597 publications

(542 citation statements)

References 82 publications

Supporting

Mentioning

512

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, in addition to protecting the AMPA receptor GluA1 subunit, the equipotent endocannabinoid modulator protected the ability of GluA1 to be phosphorylated by cAMP-dependent protein kinase at residue serine-845, moreso than the AM6702 treatment. This posttranslational modification of AMPA channels has been found to increase their open probability [59], to regulate their cell surface expression [60], and to promote long-term potentiation and retention of spatial memory [61,62]. KA-induced disruption of the GluA1 phosphorylated state may contribute to the seizure-mediated decline in brain function.…”

Section: Discussionmentioning

confidence: 99%

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

et al. 2012

View full text Add to dashboard Cite

Advances in the understanding of the endogenous cannabinoid system have led to several therapeutic indications for new classes of compounds that enhance cannabinergic responses. Endocannabinoid levels are elevated during pathogenic conditions, and inhibitors of endocannabinoid inactivation promote such on-demand responses. The endocannabinoids anandamide and 2-arachidonoyl glycerol have been implicated in protective signaling against excitotoxic episodes, including seizures. To better understand modulatory pathways that can exploit such responses, we used the new generation compound AM6701 that blocks both the anandamide-deactivating enzyme fatty acid amide hydrolase (FAAH) and the 2-arachidonoyl glycerol-deactivating enzyme monoacylglycerol lipase (MAGL) with equal potency. Also studied was the structural isomer AM6702 which is 44-fold more potent for inhibiting FAAH versus MAGL. When applied before and during kainic acid (KA) exposure to cultured hippocampal slices, AM6701 protected against the resulting excitotoxic events of calpain-mediated cytoskeletal damage, loss of presynaptic and postsynaptic proteins, and pyknotic changes in neurons. The equipotent inhibitor was more effective than its close relative AM6702 at protecting against the neurodegenerative cascade assessed in the slice model. In vivo, AM6701 was also the more effective compound for reducing the severity of KA-induced seizures and protecting against behavioral deficits linked to seizure damage. Corresponding with the behavioral improvements, cytoskeletal and synaptic protection was elicited by AM6701, as found in the KA-treated hippocampal slice model. It is proposed that the influence of AM6701 on FAAH and MAGL exerts a synergistic action on the endocannabinoid system, thereby promoting the protective nature of cannabinergic signaling to offset excitotoxic brain injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

et al. 2012

View full text Add to dashboard Cite

show abstract

“…In general, increased phosphorylation leads to LTP and decreased phosphorylation leads to LTD 129,130 . CaMKII and PKC can phosphorylate the GluA1 subunit at S831 131 , which increases the conductance of homomeric GluA1 and GluA1/2 heteromers in the presence of TARPs 132 , while PKA phosphorylates GluA1 at S845, increasing the peak conductance and open probability of the channel 133 . Knock-in mice expressing GluA1 or GluA2 subunits mutated to non-phosphorylatable or phosphomimetic residues have demonstrated that phosphorylation of GluA1 by CaMKII or PKA is necessary for full hippocampal LTP expression 134 , while dephosphorylation of the PKA site in GluA1 is required for LTD 46 .…”

Section: Ampar Phosphorylationmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

View full text Add to dashboard Cite

General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. PrefaceAMPARs are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity, and in response to neuronal stress in disease. Recently, the subunit-dependence of AMPAR trafficking has been questioned leading to a reappraisal of the field. Here we review what is known, uncertain, conjectured and unknown about the roles of individual subunits and how they impact on AMPAR assembly, trafficking and function under normal and pathological conditions. IntroductionAMPA receptors (AMPARs) are a subtype of ionotropic glutamate receptors that are the 'work-horses' of fast excitatory neurotransmission in the CNS. Developmentallyand activity-regulated changes in the numbers and properties of AMPARs localized at the postsynaptic membrane are essential for excitatory synapse formation, stabilization, synaptic plasticity and neural circuit formation. Consequently, the logistics of the delivery, retention and removal of individual AMPARs with defined subunit compositions at specific synapses is highly complex. A typical cortical or hippocampal pyramidal neuron contains on the order of 10,000 synapses and the AMPARs at each synapse are independently and dynamically regulated in response to developmental cues, synaptic activity and environmental stresses. Furthermore, defects in the processes that control AMPAR assembly, trafficking and synaptic expression are intimately linked to psychiatric and neurological conditions, and also with cognitive decline in neurodegenerative diseases. Remarkable progress has been achieved in understanding how AMPAR trafficking, is orchestrated by a large array of AMPAR interacting proteins. These studies have established a set of hierarchical subunit-specific rules that control AMPAR trafficking under basal and activity-dependent conditions. Furthermore, there has been a growing appreciation that subunit composition can tune the properties of AMPARs to specific conditions. Nonetheless, how AMPARs comprising different subunits are differentially trafficked to control synaptic development, stabilisation and plasticity is a key unanswered question. Here, we provide an overview of the current state of knowledge of subunit-specific AMPAR trafficking and outline what we believe to be the key unresolved questions in the field. 2 Subunit-specific traffickingMost AMPARs are heterotetrameric assemblies of combinations of the subunits GluA1, GluA2, GluA3 and GluA4. AMPARs are expressed in both neurons and glia throughout the CNS 1 and have a turnover time of between 10 hours and 2 days depending on the type of neuron and developmental stage 2,3 . Each subunit has an identical membrane topology and c...

show abstract

“…AKAP-bound PKA enhances the phosphorylation of Ser 845 in the cytoplasmic tail of GluR1 and is believed to stabilize AMPA currents 11,12 . Conversely, the AKAP-bound phosphatase PP2B may mediate the rundown of GluR1 currents 13 (Fig.…”

Section: Functional Characterization Of Akap79-depleted Cellsmentioning

confidence: 99%

“…1d, black triangles). Importantly, downregulation of the GluR1 current was rescued following expression of the murine orthologue AKAP150 that is refractory to pSAKAP79i RNAi ( Signalling to AMPA channels requires anchored PP2B and SAP97 AKAP-bound PKA enhances the phosphorylation of Ser 845 in the cytoplasmic tail of GluR1 and is believed to stabilize AMPA currents 11,12 . Conversely, the AKAP-bound phosphatase PP2B may mediate the rundown of GluR1 currents 13 (Fig.…”

Section: Functional Characterization Of Akap79-depleted Cellsmentioning

confidence: 99%

Distinct enzyme combinations in AKAP signalling complexes permit functional diversity

2005

View full text Add to dashboard Cite

Specificity in cell signalling can be influenced by the targeting of different enzyme combinations to substrates. The A-kinase anchoring protein AKAP79/150 is a multivalent scaffolding protein that coordinates the subcellular localization of second-messenger-regulated enzymes, such as protein kinase A, protein kinase C and protein phosphatase 2B. We developed a new strategy that combines RNA interference of the endogenous protein with a protocol that selects cells that have been rescued with AKAP79/150 forms that are unable to anchor selected enzymes. Using this approach, we show that AKAP79/150 coordinates different enzyme combinations to modulate the activity of two distinct neuronal ion channels: AMPA-type glutamate receptors and M-type potassium channels. Utilization of distinct enzyme combinations in this manner provides a means to expand the repertoire of cellular events that the same AKAP modulates.Cellular regulation must be accomplished through the synchronized actions of a limited number of gene products, as the number of mammalian genes that are required to sustain life is significantly less than was originally anticipated 1,2 . Signal-transduction pathways are created when enzymes, often with broad substrate specificities, act sequentially to evoke cellular responses 3 . Restricting the subcellular localization of these enzymes with scaffolding proteins contributes to the fidelity of each response 4 . Prototypic examples of these are the A-kinase anchoring proteins (AKAPs) that target the cyclic-AMP-dependent protein kinase (protein kinase A, PKA) and other enzymes to defined subcellular locations 5 .AKAP signalling complexes often include signal-transduction and signal-termination enzymes to regulate the forward and backward steps of a given process. The notion of multivalent anchoring proteins was first proposed for the AKAP79 family, which consists of a group of three structurally similar orthologues: human AKAP79, murine AKAP150 and bovine AKAP75 (ref. 6). These AKAPs contain binding sites for PKA, the calcium/ phospholipid-dependent kinase (protein kinase C, PKC) and the calcium/calmodulindependent phosphatase (protein phosphatase 2B, PP2B) 7 . They are tethered to the inner face of the plasma membrane, where they can respond to the generation of second messengers, such as cAMP, calcium and phospholipid 7 . Functional studies have shown that this AKAP family controls the phosphorylation status and action of several ion channels, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors, L-type calcium channels, aquaporin water channel, and M-type potassium channels [8][9][10] . One theory that accounts for this diversity of action is that unique combinations of anchored enzymes are recruited to individual ion channels. We tested this hypothesis in cells in which the endogenous anchoring protein was silenced and replaced with AKAP forms that were unable to anchor selected binding partners. Results Functional characterization of AKAP79-depleted cellsPl...

show abstract

Control of GluR1 AMPA Receptor Function by cAMP-Dependent Protein Kinase

Cited by 597 publications

References 82 publications

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

Synaptic AMPA receptor composition in development, plasticity and disease

Distinct enzyme combinations in AKAP signalling complexes permit functional diversity

Contact Info

Product

Resources

About