Autoinactivation of Neuronal AMPA Receptors via Glutamate-Regulated TARP Interaction

Morimoto-Tomita, Megumi; Zhang, Wei; Straub, Christoph; Cho, Chang-Hoon; Kim, Kwang S.; Howe, James R.; Tomita, Susumu

doi:10.1016/j.neuron.2008.11.009

Cited by 80 publications

(106 citation statements)

References 53 publications

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“…Glutamatergic hypofunction is often hypothesized to be a significant contributor to the pathophysiology of schizophrenia. We show here that PDE11A KO mice show lower levels of phospho-GluR1 (Ser845) and of the transmembrane AMPA receptor regulatory proteins stargazin (γ2) and γ8 in ventral hippocampus, all of which would lead to decreased AMPA receptor function (41). Sexdependent effects on TARP expression were also noted in prefrontal cortex (Fig.…”

Section: Pde11a Ko Mice Show Anatomical and Biochemical Dysfunctionmentioning

confidence: 57%

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Kelly

Logue

Brennan

et al. 2010

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

156

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Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A −/− knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a twoto threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatricdisease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate α-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (γ2) and γ8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.

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Section: Pde11a Ko Mice Show Anatomical and Biochemical Dysfunctionmentioning

confidence: 57%

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Kelly

Logue

Brennan

et al. 2010

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

156

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“…It has been successfully applied to all major receptor domains (30)(31)(32)(33)(34). Here, we extend this approach to the LBD of the nonfunctional delta2 subunit, providing evidence that delta2 subunits can form functional ion channels that are able to sense the conformational status of an integral LBD, i.e., that can be gated by ligands.…”

Section: Discussionmentioning

confidence: 93%

The glutamate receptor subunit delta2 is capable of gating its intrinsic ion channel as revealed by ligand binding domain transplantation

Schmid

Kott²,

Sager³

et al. 2009

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

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The family of ionotropic glutamate receptors includes 2 subunits, delta1 and delta2, the physiological relevance of which remains poorly understood. Both are nonfunctional in heterologous expression systems, although the isolated, crystallized ligand binding domain (LBD) of delta2 is capable of binding D-serine. To investigate these seemingly contradictory observations we tested whether delta receptors can be ligand gated at all. We used a strategy that replaced the native LBD of delta2 by a proven glutamate-binding LBD. Test transplantations between ␣-amino-3-hydroxy-5-methylisoxazole propionate (AMPA) and kainate receptors (GluR1 and GluR6, respectively) showed that this approach can produce functional chimeras even if only one part of the bipartite LBD is swapped. Upon outfitting delta2 with the LBD of GluR6, the chimera formed glutamate-gated ion channels with low Ca 2؉ permeability and unique rectification properties. Ligandinduced conformational changes can thus gate delta2, suggesting that the LBD of this receptor works fundamentally differently from that of other ionotropic glutamate receptors.orphan receptor ͉ AMPA receptor ͉ kainate receptor ͉ chimeric receptors ͉ ligand binding domain

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“…Furthermore, dynamic AMPAR-TARP interactions have also been recently demonstrated to underlie by ability of AMAPRs to support high-frequency stimulation despite undergoing desentisiation 117 . A general consensus is that agonist binding reduces AMPAR affinity for Stargazin 98,117,118 (but see 119,120 ) allowing AMPARs to diffuse away from the synaptically-anchored Stargazin. This loss of desensitised AMPARs from the postsynaptic density frees up 'slots' for non-desensitised AMPARs, which maintains synaptic transmission 117 .…”

Section: Ampar Auxiliary Subunitsmentioning

confidence: 99%

Synaptic AMPA receptor composition in development, plasticity and disease

2016

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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...

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Autoinactivation of Neuronal AMPA Receptors via Glutamate-Regulated TARP Interaction

Cited by 80 publications

References 53 publications

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

The glutamate receptor subunit delta2 is capable of gating its intrinsic ion channel as revealed by ligand binding domain transplantation

Synaptic AMPA receptor composition in development, plasticity and disease

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