Mechanisms of zinc modulation of olfactory bulb AMPA receptors
Mechanisms of zinc modulation of olfactory bulb AMPA receptors
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DOI：
10.1016/j.neuroscience.2019.05.001
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发表时间：
2019-07-01
期刊：
影响因子：
3.3
通讯作者：
Trombley, Paul Q.
中科院分区：
文献类型：
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作者：
Blakemore, Laura J.;Trombley, Paul Q.
离子型谷氨酸受体的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）亚型介导最快的兴奋性传递。谷氨酸与AMPA受体（AMPAR）的结合导致大多数AMPAR迅速和完全脱敏，其脱敏动力学影响突触时序。因此，改变AMPAR脱敏的因素影响突触传递。突触释放的锌就是这样一个因素。锌是一种神经调质，对包括嗅球（OB）在内的许多脑区的氨基酸受体和突触传递有影响。我们以前在OB中已经表明，锌在低浓度（30 μ M，100 μ M）下增强AMPAR介导的电流，并在较高浓度（1 mM）下抑制它们。据推测，锌通过减少受体脱敏来增强AMPAR。在这里，我们使用环噻嗪（CTZ），一种阻断AMPAR脱敏的药物，来确定锌介导的增强和/或AMPA诱发电流的抑制是否反映了AMPAR脱敏的变化。锌在很大程度上具有双相浓度依赖性效应在OB AMPAR。CTZ完全阻断锌的增强作用，但对抑制作用无显著影响。100 μ M锌对AMPAR介导电流的增强程度与AMPAR脱敏程度的定量测量（AMPA诱发电流的稳态与峰值[S：P]比）之间存在显著负相关，但1 mM锌对电流的抑制程度与S：P比之间无相关性。总之，这些研究结果表明，低锌浓度增强大鼠OB AMPAR通过减少受体脱敏，但较高的锌浓度的抑制作用是由一个单独的机制介导的。由Elsevier Ltd代表IBRO出版。
The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptors mediates most fast excitatory transmission. Glutamate binding to AMPA receptors (AMPARs) causes most AMPARs to rapidly and completely desensitize, and their desensitization kinetics influence synaptic timing. Thus, factors that alter AMPAR desensitization influence synaptic transmission. Synaptically released zinc is such a factor. Zinc is a neuromodulator with effects on amino acid receptors and synaptic transmission in many brain regions, including the olfactory bulb (OB). We have previously shown in the OB that zinc potentiates AMPAR-mediated currents at low concentrations (30 mu M, 100 mu M) and inhibits them at a higher concentration (1 mM). It has been hypothesized that zinc potentiates AMPARs by decreasing receptor desensitization. Here, we used cyclothiazide (CTZ), a drug that blocks AMPAR desensitization, to determine whether zinc-mediated potentiation and/or inhibition of AMPA-evoked currents reflect(s) changes in AMPAR desensitization. Zinc largely had biphasic concentration-dependent effects at OB AMPARs. CTZ completely blocked potentiation by zinc but had no significant effect on inhibition. There was a significant negative correlation between the degree of potentiation of AMPAR-mediated currents by 100 mu M zinc and a quantitative measure of the degree of AMPAR desensitization (the steady-state to peak [S:P] ratio of AMPA-evoked currents), but no correlation between the degree of current inhibition by 1 mM zinc and the S:P ratio. Together, these findings suggest that low zinc concentrations potentiate rat OB AMPARs by decreasing receptor desensitization, but that the inhibitory effects of higher zinc concentrations are mediated by a separate mechanism. Published by Elsevier Ltd on behalf of IBRO.