Chemical interplay in the mechanism of partial agonist activation in α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
Chemical interplay in the mechanism of partial agonist activation in α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
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DOI：
10.1021/bi702004b
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发表时间：
2008-01-08
期刊：
影响因子：
2.9
通讯作者：
Jayaraman, Vasanthi
中科院分区：
文献类型：
--
作者：
Mankiewicz, Kimberly A.;Rambhadran, Anu;Jayaraman, Vasanthi
alpha-Aniino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, one subtype in the family of ionotropic glutamate receptors, are the main receptors responsible for excitatory signaling in the mammalian central nervous system. Previous studies utilitizing the isolated ligand binding domain of these receptors have provided insight into the role of specific ligand-protein interactions in mediating receptor activation. However, these studies relied heavily on the partial agonist kainate, in which the (x-amine group is constrained in a pyrrolidine ring. Here we have studied a series of substituted and unsubstituted willardiines with primary (x-amine groups similar to that of the full agonist glutamate whose activation can be varied depending on the size of the substituent. The specific ligand-protein interactions in the mechanism of partial agonism in this subtype were investigated using vibrational spectroscopy, and the large-scale conformational changes in the ligand binding domain were studied with fluorescence resonance energy transfer (FRET). These investigations show that the strength of the interaction at the a-amine group correlates with the extent of cleft closure and extent of activation, with the agonist of higher efficacy showing larger cleft closure and stronger interactions at this group, suggesting that this is one of the mechanisms by which the agonist controls receptor activation.
