Transmembrane AMPA receptor regulatory protein regulation of competitive antagonism: a problem of interpretation
Transmembrane AMPA receptor regulatory protein regulation of competitive antagonism: a problem of interpretation
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DOI：
10.1113/jphysiol.2011.219485
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发表时间：
2011-11-01
影响因子：
5.5
通讯作者：
Bowie, Derek
中科院分区：
文献类型：
--
作者：
MacLean, David M.;Bowie, Derek
突触AMPA受体受到跨膜AMPA受体调节蛋白（TARPs）家族的极大影响，这些蛋白控制运输、通道门控和药理学。原型TARP，stargazin（或γ 2），转移了几种AMPAR选择性化合物的阻断能力，包括常用的喹喔啉二酮拮抗剂，CNQX和NBQX。Stargazin对CNQX的作用特别有趣，因为它不仅明显降低了阻断的效力，就像NBQX一样，而且还使其成为部分激动剂。鉴于此，已推测CNQX的激动剂行为是其对AMPAR-TARP复合物的较弱阻断作用的原因。在这里，我们表明情况并非如此。Stargazin对CNQX拮抗作用的明显作用几乎完全可以通过增加对L-谷氨酸（L-Glu）的表观亲和力来解释，L-谷氨酸是AMPAR突触处的完全激动剂和神经递质。部分激动作用最多起次要作用，但不是通过通道门控本身，而是因为CNQX使AMPAR脱敏。我们的研究表明，CNQX最好被认为是一个非竞争性拮抗剂在突触由于占主导地位的非平衡条件。因此，CNQX主要报告可用于激活的AMPAR的比例，但也可能通过受体脱敏施加额外的阻断。
Synaptic AMPA receptors are greatly influenced by a family of transmembrane AMPA receptor regulatory proteins (TARPs) which control trafficking, channel gating and pharmacology. The prototypical TARP, stargazin (or gamma 2), shifts the blocking ability of several AMPAR-selective compounds including the commonly used quinoxalinedione antagonists, CNQX and NBQX. Stargazin's effect on CNQX is particularly intriguing as it not only apparently lowers the potency of block, as with NBQX, but also renders it a partial agonist. Given this, agonist behaviour by CNQX has been speculated to account for its weaker blocking effect on AMPAR-TARP complexes. Here we show that this is not the case. The apparent effect of stargazin on CNQX antagonism can be almost entirely explained by an increase in the apparent affinity for L-glutamate (L-Glu), a full agonist and neurotransmitter at AMPAR synapses. Partial agonism at best plays a minor role but not through channel gating per se but rather because CNQX elicits AMPAR desensitization. Our study reveals that CNQX is best thought of as a non-competitive antagonist at glutamatergic synapses due to the predominance of non-equilibrium conditions. Consequently, CNQX primarily reports the proportion of AMPARs available for activation but may also impose additional block by receptor desensitization.