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: 15.05). 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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    • "Subsequently, a family of six transmembrane AMPAR regulatory proteins (TARPs) were defined that modify channel trafficking, gating, and pharmacology (Kato and Bredt, 2007; Tomita et al., 2003). Cornichons (CNIH-2/3) are a family of AMPAR auxiliary subunits that control export of AMPARs from the endoplasmic reticulum (Harmel et al., 2012; Schwenk et al., 2009) and associate with synaptic AMPARs to modulate channel kinetics (Jackson and Nicoll, 2011; Kato et al., 2010; Schwenk et al., 2009; Yan and Tomita, 2012). Recent proteomic studies have further expanded the complement of AMPARassociated proteins. "
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    ABSTRACT: AMPA receptor (AMPAR) complexes contain auxiliary subunits that modulate receptor trafficking and gating. In addition to the transmembrane AMPAR regulatory proteins (TARPs) and cornichons (CNIH-2/3), recent proteomic studies identified a diverse array of additional AMPAR-associated transmembrane and secreted partners. We systematically surveyed these and found that PORCN and ABHD6 increase GluA1 levels in transfected cells. Knockdown of PORCN in rat hippocampal neurons, which express it in high amounts, selectively reduces levels of all tested AMPAR complex components. Regulation of AMPARs is independent of PORCN’s membrane-associated O-acyl transferase activity. PORCN knockdown in hippocampal neurons decreases AMPAR currents and accelerates desensitization and leads to depletion of TARP γ-8 from AMPAR complexes. Conditional PORCN knockout mice also exhibit specific changes in AMPAR expression and gating that reduce basal synaptic transmission but leave long-term potentiation intact. These studies define additional roles for PORCN in controlling synaptic transmission by regulating the level and composition of hippocampal AMPAR complexes.
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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: Unlabelled: 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. Video abstract:
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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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    ABSTRACT: Neuronal voltage-gated ion channels and ligand-gated synaptic receptors play a critical role in maintaining the delicate balance between neuronal excitation and inhibition within neuronal networks in the brain. Changes in expression of voltage-gated ion channels, in particular sodium, hyperpolarization-activated cyclic nucleotide-gated (HCN) and calcium channels, and ligand-gated synaptic receptors, in particular GABA and glutamate receptors, have been reported in many types of both genetic and acquired epilepsies, in animal models and in humans. In this chapter we review these and discuss the potential pathogenic role they may play in the epilepsies.
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