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    • In a previous study M ykkynen

    2022-01-07

    In a previous study (Möykkynen et al., 2003), we reported that ethanol lengthens the time needed for the AMPA receptors to recovery from desensitization in isolated hippocampal neurons. Here, we did not observe any effect of ethanol on recovery from desensitization in recombinant homomeric GluR-D receptors. The recovery from desensitization of these receptors was much faster than that of receptors in acutely isolated neurons, indicating that the conditions or receptor properties between the experiments differ substantially. The difference may reflect the differences in AMPA receptor and TARP subunits expressed in native neurons as compared with HEK-293 cells. It should be noted that τrec-values measured in this study for GluR-Di receptors are higher than those previously reported for this same subunit expressed in HEK-293 nibr (Grosskreutz et al., 2003). However, ultrafast agonist application method was used in this previous study along with excised outside-out membrane patches, giving both GluR-D flip and flop splice variants extremely fast τrec-values of around 3ms. Our agonist delivery and washout conditions were slower—that might explain the differences. Loss of cytoskeletal interactions in outside-out membrane patches leading to faster recovery kinetics might also contribute to these differences. In the present study, coexpression of stargazin did not affect recovery from desensitization, but γ4 expression slowed recovery. Interestingly, an opposite effect of stargazin on recovery from desensitization of GluR-A receptors expressed in HEK-293 cells has been reported (Priel et al., 2005), indicating that the effects of TARPs on AMPA receptors might be receptor subunit-selective. Our observation that the other TARP studied here, γ4, slows the recovery from desensitization, also suggests that the effects of TARPs on AMPA receptor function depend on the TARP subunit in question. This study shows for the first time directly that ethanol accelerates the desensitization of AMPA receptors and that coexpression of TARPs with AMPA receptors further enhances this acceleration. The findings of this study relate to the situation in the native brain because TARPs are considered to assemble with AMPA receptors in many brain areas and neuronal types (Hashimoto et al., 1999, Menuz et al., 2008, Milstein et al., 2007, Rouach et al., 2005, Tomita et al., 2003). Desensitization might have little effect on neurotransmission in mature synapses because of the fast glutamate clearance from the synaptic cleft (Clements et al., 1992). However, desensitization probably plays a role in some distinct brain areas, where synaptic currents decay at the rate of desensitization rather than deactivation (Barbour et al., 1994, Maguire, 1999, Otis et al., 1996, Trussell et al., 1993). In addition, it seems that during brain development, desensitization becomes more important in shaping the decay of excitatory postsynaptic currents as shown in mossy fiber–cerebellar granule cell synapses (Wall et al., 2002). Ethanol concentrations used in the present study (25–100mM) were relatively high but still reachable during alcohol intoxication. The acceleration of receptor desensitization shown in this study may therefore decrease AMPA receptor function in intact brain and contribute to ethanol intoxication.
    Acknowledgment
    Introduction Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS). Glutamatergic synaptic plasticity, typically induced by N-methyl-D-aspartate (NMDA) receptor activation, is manifested by long-term potentiation or depression (LTP or LTD) of the α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor-mediated synaptic current amplitude Malenka and Nicoll 1999, Malinow et al. 2000. The molecular mechanisms by which neurons can regulate postsynaptic AMPA receptor-mediated current responses may include changes in receptor number at individual synapses. Indeed, at least some aspects of excitatory synaptic plasticity in the developing and mature CNS appear to result from activity-regulated incorporation of AMPA receptors from nonsynaptic to synaptic loci (Malinow and Malenka, 2002).