Article

Hippocampal AMPA Receptor Gating Controlled by Both TARP and Cornichon Proteins

Department of Neuroscience, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Neuron (Impact Factor: 15.98). 12/2010; 68(6):1082-96. DOI: 10.1016/j.neuron.2010.11.026
Source: PubMed

ABSTRACT Transmembrane AMPA receptor regulatory proteins (TARPs) and cornichon proteins (CNIH-2/3) independently modulate AMPA receptor trafficking and gating. However, the potential for interactions of these subunits within an AMPA receptor complex is unknown. Here, we find that TARPs γ-4, γ-7, and γ-8, but not γ-2, γ-3, or γ-5, cause AMPA receptors to "resensitize" upon continued glutamate application. With γ-8, resensitization occurs with all GluA subunit combinations; however, γ-8-containing hippocampal neurons do not display resensitization. In recombinant systems, CNIH-2 abrogates γ-8-mediated resensitization and modifies AMPA receptor pharmacology and gating to match that of hippocampal neurons. In hippocampus, γ-8 and CNIH-2 associate in postsynaptic densities and CNIH-2 protein levels are markedly diminished in γ-8 knockout mice. Manipulating neuronal CNIH-2 levels modulates the electrophysiological properties of extrasynaptic and synaptic γ-8-containing AMPA receptors. Thus, γ-8 and CNIH-2 functionally interact with common hippocampal AMPA receptor complexes to modulate synergistically kinetics and pharmacology.

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    • "Their distinct combinatorial architecture defines the function of the AMPARs. The inner core largely determines the biophysical properties of the receptors, including agonist-triggered channel gating, ion selectivity, and permeation, or block by polyamines , and influences their biogenesis and protein processing (Bats et al., 2007; Chen et al., 2000; Cho et al., 2007; Coombs et al., 2012; Kato et al., 2010a; Schwenk et al., 2009; Soto et al., 2007; Soto et al., 2009; Studniarczyk et al., 2013; Tomita et al., 2005). The periphery of the AMPARs seems to be involved in various aspects of synapse physiology (Cantallops et al., 2000; Chen et al., 2000; Hussain et al., 2010; Siddiqui et al., 2013; von Engelhardt et al., 2010; Zhu et al., 2002). "
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    ABSTRACT: Native AMPA receptors (AMPARs) in the mammalian brain are macromolecular complexes whose functional characteristics vary across the different brain regions and change during postnatal development or in response to neuronal activity. The structural and functional properties of the AMPARs are determined by their proteome, the ensemble of their protein building blocks. Here we use high-resolution quantitative mass spectrometry to analyze the entire pool of AMPARs affinity-isolated from distinct brain regions, selected sets of neurons, and whole brains at distinct stages of postnatal development. These analyses show that the AMPAR proteome is dynamic in both space and time: AMPARs exhibit profound region specificity in their architecture and the constituents building their core and periphery. Likewise, AMPARs exchange many of their building blocks during postnatal development. These results provide a unique resource and detailed contextual data sets for the analysis of native AMPAR complexes and their role in excitatory neurotransmission.
    Neuron 09/2014; 84(1). DOI:10.1016/j.neuron.2014.08.044 · 15.98 Impact Factor
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    • "It is likely that this requires an increase in the number of AMPARs for the following reasons: first, overexpressing selected AMPAR subunits increases dendritic complexity (Hamad et al., 2011; Inglis et al., 2002); second, knocking the number of AMPARs down drastically reduces dendritic complexity (Haas et al., 2006); third, overexpression of γ-8 increases the number of AMPARs in the plasma membrane whereas in γ-8 −/− mice AMPAR-mediated synaptic transmission is severely impaired because of a loss of GluA2 and GluA3 (Fukaya et al., 2006; Hashimoto et al., 1999; Menuz et al., 2009; Rouach et al., 2005). The growth-promoting TARPs identified in the present study have one common feature: they enrich in the postsynaptic site or postsynaptic density fraction as revealed by electron microscopy and biochemistry (Ferrario et al., 2011; Fukaya et al., 2006; Kato et al., 2010). Morever, γ-8 tends to deliver AMPARs to synaptic sites (Sumioka et al., 2011). "
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    ABSTRACT: 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.
    Development 03/2014; 141(8). DOI:10.1242/dev.099697 · 6.27 Impact Factor
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    • "These proteins differentially regulate AMPA-receptor channel gating and are involved in subunit folding, assembly, surface expression, and clustering and anchoring of AMPA receptors at synapses (Diaz, 2010; Jackson & Nicoll, 2011). Transmembrane AMPA receptor regulatory proteins: TARPs are a family of proteins— including stargazin (c2), c3, c 4, c5, c7, and c8—with distinct and complementary expression patterns in both neurons and glia in the developing and mature CNS (Tomita et al., 2003; Kato et al., 2010). Stargazin (c2) was the first TARP identified when a mutation in its gene (Cacng2) was found to cause the stargazer mouse, which manifests spontaneous absence-like seizures with generalized spike-and-wave discharges as well as having cerebellar ataxia (Letts et al., 1998). "
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    Advances in Experimental Medicine and Biology 01/2014; 813:211-29. DOI:10.1007/978-94-017-8914-1_17 · 2.01 Impact Factor
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