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


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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    • "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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    • "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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