AMPA Receptor Subunit-Specific Regulation by a Distinct Family of Type II TARPs

Kato, Akihiko; Siuda, Edward R.; Nisenbaum, Eric S.; Bredt, David S.

doi:10.1016/j.neuron.2008.07.034

Cited by 114 publications

(156 citation statements)

References 48 publications

(98 reference statements)

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“…TARP γ-2, which is expressed in all neuronal types in the cerebellum, has been shown to determine the number of synaptic AMPARs at mossy fiber-to-CGN synapses (3,4,14), parallel fiber-to-PC synapses and climbing fiber-to-PC synapses (14,15), parallel fiber-to-SC synapses (17,22), and parallel fiber-to-Golgi cell synapses (15). Less clear is the role of the type II TARP γ-7, which is expressed, along with γ-2 and often other TARP family members, in CGNs, PCs, and SCs (11,16). In this study, we undertook an examination of the specific roles that this TARP family member may play in excitatory synaptic transmission among these cerebellar cell types and their role in motor behavior.…”

Section: Discussionmentioning

confidence: 99%

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Yamazaki

Pichon²,

Jackson

et al. 2015

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

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Transmembrane AMPA receptor regulatory proteins (TARPs) play an essential role in excitatory synaptic transmission throughout the central nervous system (CNS) and exhibit subtype-specific effects on AMPA receptor (AMPAR) trafficking, gating, and pharmacology. The function of TARPs has largely been determined through work on canonical type I TARPs such as stargazin (TARP γ-2), absent in the ataxic stargazer mouse. Little is known about the function of atypical type II TARPs, such as TARP γ-7, which exhibits variable effects on AMPAR function. Because γ-2 and γ-7 are both strongly expressed in multiple cell types in the cerebellum, we examined the relative contribution of γ-2 and γ-7 to both synaptic transmission in the cerebellum and motor behavior by using both the stargazer mouse and a γ-7 knockout (KO) mouse. We found that the loss of γ-7 alone had little effect on climbing fiber (cf) responses in Purkinje neurons (PCs), yet the additional loss of γ-2 all but abolished cf responses. In contrast, γ-7 failed to make a significant contribution to excitatory transmission in stellate cells and granule cells. In addition, we generated a PC-specific deletion of γ-2, with and without γ-7 KO background, to examine the relative contribution of γ-2 and γ-7 to PC-dependent motor behavior. Selective deletion of γ-2 in PCs had little effect on motor behavior, yet the additional loss of γ-7 resulted in a severe disruption in motor behavior. Thus, γ-7 is capable of supporting a component of excitatory transmission in PCs, sufficient to maintain essentially normal motor behavior, in the absence of γ-2.cerebellum | AMPA receptors | TARPs | stargazer | motor behavior N euronal excitability is controlled by two broad classes of ion channels: voltage-gated and ligand-gated. It is well established that voltage-gated channels are not only composed of pore-forming subunits but auxiliary subunits as well, which are not part of the pore, but control many important aspects of channel function, such as trafficking and gating (1, 2). In contrast, ligand-gated ion channels were thought to function independently of auxiliary subunits. The discovery of the tetraspanning membrane protein stargazin, also referred to as γ-2, which is mutated in the ataxic stargazer (stg) mouse, changed this view. Cerebellar granule neurons (CGNs), which express high levels of stargazin, were found to lack surface AMPA-type glutamate receptors (AMPARs) in the stg mouse (3, 4). Stargazin not only controls the trafficking of AMPARs, but also controls AMPAR gating (5-10), indicating that it satisfies all of the criteria of auxiliary subunits. Stargazin is a member of a family of proteins referred to as transmembrane AMPAR regulatory proteins (TARPs) and consists of the following members: canonical type I TARPs (γ-2, γ-3, γ-4, and γ-8) and atypical type II TARPs (γ-5 and γ-7), which differ in their amino acid sequence and uniquely regulate AMPAR trafficking, gating, and neuropharmacology (7).Of particular interest is TARP γ-7, which is expressed throughout the brain...

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Section: Discussionmentioning

confidence: 99%

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Yamazaki

Pichon²,

Jackson

et al. 2015

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

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“…Therefore, it seems likely that factors other than subunit and flip-flop type contribute to ampakine efficacy. Of particular interest are the TARPs of which six variants (␥2-␥5, ␥7, ␥8) have now been shown to associate with AMPA receptors Kato et al, 2008) and for which regional expression appears to be more distinctive than for receptor subunits. In the adult brain, for example, the TARPs ␥3 and ␥8 are strongly dominant in hippocampal neurons, whereas ␥4 is largely absent, and an inverse pattern is found in the thalamus (Moss et al, 2003;Tomita et al, 2003).…”

mentioning

confidence: 99%

Modulation of Agonist Binding to AMPA Receptors by 1-(1,4-Benzodioxan-6-ylcarbonyl)piperidine (CX546): Differential Effects across Brain Regions and GluA1–4/Transmembrane AMPA Receptor Regulatory Protein Combinations

Montgomery

Kessler²,

Arai³

2009

J Pharmacol Exp Ther

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Ampakines are cognitive enhancers that potentiate ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents and synaptic responses by slowing receptor deactivation. Their efficacy varies greatly between classes of neurons and brain regions, but the factor responsible for this effect remains unclear. Ampakines also increase agonist affinity in binding tests in ways that are related to their physiological action. We therefore examined 1) whether ampakine effects on agonist binding vary across brain regions and 2) whether they differ across receptor subunits expressed alone and together with transmembrane AMPA receptor regulatory proteins (TARPs), which associate with AMPA receptors in the brain. We found that the maximal increase in agonist binding (E max ) caused by the prototypical ampakine 1-(1,4-benzodioxan-6-ylcarbonyl)-piperidine (CX546) differs significantly between brain regions, with effects in hippocampus and cerebellum being nearly three times larger than that in thalamus, brainstem, and striatum, and cortex being intermediate. These differences can be explained at least in part by regional variations in receptor subunit and TARP expression because combinations prevalent in hippocampus (GluA2 with TARPs ␥3 and ␥8) exhibited E max values nearly twice those of combinations abundant in thalamus (GluA4 with ␥2 or ␥4). TARPs seem to be critical because GluA2 and GluA4 alone had comparable E max and also because hippocampal and thalamic receptors had similar E max after solubilization with Triton X-100, which probably removes associated proteins. Taken together, our data suggest that variations in physiological drug efficacy, such as the 3-fold difference previously seen in recordings from hippocampus versus thalamus, may be explained by region-specific expression of GluA1-4 as well as TARPs.Ampakines are benzamide compounds that allosterically potentiate ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents, prolong synaptic responses (Arai et al., , 2002Arai and Kessler, 2007), facilitate long-term potentiation (Arai et al., 2004), and enhance memory encoding in animals and humans (Staubli et al., 1994;Lynch et al., 1997;Hampson et al., 1998). They also have shown therapeutic potential for various pathological conditions such as Alzheimer's disease, schizophrenia, and depression (Lynch, 2006).In two earlier studies, we found that ampakine effects vary greatly between neurons. In hippocampus, 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine (CX546) was nearly 10-fold more effective in prolonging excitatory postsynaptic currents in pyramidal cells than in interneurons or in stratum radiatum giant cells, an ectopic version of pyramidal cells . Major differences were likewise seen between hippocampal and thalamic neurons, i.e., prolongation of excitatory postsynaptic current duration by CX546 was approximately 3-fold larger in hippocampal CA1 pyramidal cells than in two subdivisions of the thalamus . Understanding the causes for these differences is important for an...

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“…We hypothesized that overexpressed type I TARPs could shuttle more endogenous AMPARs to the plasma membrane, whereas overexpressed type II TARPs could only modulate the function of already existing AMPARs (Kato et al, 2008). These additional or more active receptors might cause a higher sensitivity to endogenous glutamate (ambient or released from developing synapses), which in turn will promote neuronal growth.…”

Section: Expression Of Tarps In Developing Rat Neocortexmentioning

confidence: 99%

“…In Xenopus oocytes, the co-expression of type I TARPs has been shown to potentiate AMPAR currents, and the extent of the TARP-mediated increase in agonist-induced responses is highly dependent on both the TARP and the AMPAR subunits . The type II TARPs γ-5 and γ-7 (also known as Cacng5 and Cacng7) do not traffic AMPAR, they only modulate AMPAR channel function (Kato et al, 2008). γ-5 is expressed in cerebellar neurons and has been shown to interact with GluA1, GluA4 (also known as Gria4) and edited GluA2 (also known as Gria2) (Soto et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Type I TARPs promote dendritic growth of early postnatal neocortical pyramidal cells in organotypic cultures

et al. 2014

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The ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate glutamate receptors (AMPARs) have been implicated in the establishment of dendritic architecture. The transmembrane AMPA receptor regulatory proteins (TARPs) regulate AMPAR function and trafficking into synaptic membranes. In the current study, we employ type I and type II TARPs to modulate expression levels and function of endogenous AMPARs and investigate in organotypic cultures (OTCs) of rat occipital cortex whether this influences neuronal differentiation. Our results show that in early development [5-10 days in vitro (DIV)] only the type I TARP γ-8 promotes pyramidal cell dendritic growth by increasing spontaneous calcium amplitude and GluA2/3 expression in soma and dendrites. Later in development (10-15 DIV), the type I TARPs γ-2, γ-3 and γ-8 promote dendritic growth, whereas γ-4 reduced dendritic growth. The type II TARPs failed to alter dendritic morphology. The TARP-induced dendritic growth was restricted to the apical dendrites of pyramidal cells and it did not affect interneurons. Moreover, we studied the effects of short hairpin RNA-induced knockdown of endogenous γ-8 and showed a reduction of dendritic complexity and amplitudes of spontaneous calcium transients. In addition, the cytoplasmic tail (CT) of γ-8 was required for dendritic growth. Single-cell calcium imaging showed that the γ-8 CT domain increases amplitude but not frequency of calcium transients, suggesting a regulatory mechanism involving the γ-8 CT domain in the postsynaptic compartment. Indeed, the effect of γ-8 overexpression was reversed by APV, indicating a contribution of NMDA receptors. Our results suggest that selected type I TARPs influence activity-dependent dendritogenesis of immature pyramidal neurons.

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AMPA Receptor Subunit-Specific Regulation by a Distinct Family of Type II TARPs

Cited by 114 publications

References 48 publications

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Relative contribution of TARPs γ-2 and γ-7 to cerebellar excitatory synaptic transmission and motor behavior

Modulation of Agonist Binding to AMPA Receptors by 1-(1,4-Benzodioxan-6-ylcarbonyl)piperidine (CX546): Differential Effects across Brain Regions and GluA1–4/Transmembrane AMPA Receptor Regulatory Protein Combinations

Type I TARPs promote dendritic growth of early postnatal neocortical pyramidal cells in organotypic cultures

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