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    • br Acknowledgements This work was supported by Programme Gra

    2023-09-16


    Acknowledgements This work was supported by Programme Grants from the MRC and the Wellcome Trust (SGC-C and MF). CB was in receipt of a Marie Curie Intra-European Fellowship during part of this work. We thank past and present members of our group for numerous valuable discussions throughout these studies.
    Main Text Moreover, receptor gating will shape the dynamics of synaptic transmission, contributing to paired-pulse or multiple-pulse depression (Colquhoun et al., 1992). If the extent of desensitization is large and the recovery from desensitization is slow, cumulative desensitization of AMPARs may occur during repetitive activation of excitatory synapses. The contribution of AMPAR desensitization to synaptic depression is particularly profound at large synapses with high release probability and multiple closely spaced release sites, such as auditory calyx synapses (Trussell et al., 1993). It is generally thought that receptor gating is determined by the subunit composition of the postsynaptic receptors (Geiger et al., 1995, Lambolez et al., 1996). AMPARs are tetramers comprised of four different types of subunits, designated as GluR-A to -D or GluR1 to -4 (Hollmann, 1999; or GluA1 to -4 in a new nomenclature). Each subunit exists in differentially spliced versions (e.g., the alternatively spliced flip and flop versions) and in RNA-edited variants (e.g., Q/R-site and R/G-site variants). The presence or absence of the GluR-B subunit and Q/R-site editing determine the Ca2+ permeability of AMPARs, whereas subunit expression, alternative flip-flop splicing, and R/G-site editing all modulate gating kinetics. Although the properties of native and recombinant AMPARs should be identical, subtle differences were previously noted. For example, both deactivation and desensitization time course of recombinant AMPARs expressed in Xenopus oocytes (Mosbacher et al., 1994) and mammalian host TH588 (e.g., human embryonic kidney cells) are consistently faster than those of native AMPARs examined under similar conditions (Colquhoun et al., 1992, Geiger et al., 1995). Conversely, subtle differences in gating kinetics between native AMPARs cannot be easily traced back to subunit composition, alternative splicing, or R/G-site editing in the corresponding neurons. For example, the time course of recovery from desensitization has a slow component in dentate gyrus granule cells, but not in CA1 pyramidal neurons (Colquhoun et al., 1992), without any major differences in mRNA expression between the two types of cells (Geiger et al., 1995). What is the explanation for these discrepancies between native and recombinant receptors? For voltage-gated ion channels, such as Na+, K+, and Ca2+ channels, it is well established that auxiliary β subunits provide a mechanism for the fine-tuning of channel gating, particularly inactivation. Accumulating evidence now suggests that auxiliary subunits provide a similar fine-tuning of AMPAR gating. The first remarkable example was the discovery of the transmembrane AMPAR regulatory proteins (TARPs; Chen et al., 2000). The starting point of the findings was the stargazer mouse, which exhibits seizures and cerebellar ataxia (Table 1). Detailed analysis of this mouse revealed that loss of a protein designated as stargazin (or TARP γ-2 in a new nomenclature) was responsible for this highly characteristic phenotype. Based on sequence similarity, eight stargazin-related proteins were identified. While two of them (γ-1, γ-6) are thought to be Ca2+ channel subunits, all the others (γ-2, γ-3, γ-4, γ-5, γ-7, and γ-8) have been demonstrated to be auxiliary subunits of AMPARs. When coexpressed with principal subunits, TARPs have multiple effects on AMPARs. First, they promote the surface expression of AMPARs (Chen et al., 2000). Second, they regulate the gating of AMPARs, typically prolonging the deactivation and desensitization of AMPARs in parallel (Tomita et al., 2005, Milstein et al., 2007; see Kato et al., 2008, regarding the distinct role of γ-5). Finally, they affect the pore properties, reducing the sensitivity to intracellular polyamines and increasing the single-channel conductance (Soto et al., 2007).