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NMDA 受体的偏倚调节剂控制通道开放和离子选择性。

Biased modulators of NMDA receptors control channel opening and ion selectivity.

机构信息

Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.

Virginia Tech Carilion Research Institute, Roanoke, VA, USA.

出版信息

Nat Chem Biol. 2020 Feb;16(2):188-196. doi: 10.1038/s41589-019-0449-5. Epub 2020 Jan 20.

DOI:10.1038/s41589-019-0449-5
PMID:31959964
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6986806/
Abstract

Allosteric modulators of ion channels typically alter the transitions rates between conformational states without changing the properties of the open pore. Here we describe a new class of positive allosteric modulators of N-methyl D-aspartate receptors (NMDARs) that mediate a calcium-permeable component of glutamatergic synaptic transmission and play essential roles in learning, memory and cognition, as well as neurological disease. EU1622-14 increases agonist potency and channel-open probability, slows receptor deactivation and decreases both single-channel conductance and calcium permeability. The unique functional selectivity of this chemical probe reveals a mechanism for enhancing NMDAR function while limiting excess calcium influx, and shows that allosteric modulators can act as biased modulators of ion-channel permeation.

摘要

变构调节剂通常改变构象状态之间的转变速率，而不改变开放孔的性质。在这里，我们描述了一类新的 N-甲基-D-天冬氨酸受体 (NMDAR) 的正变构调节剂，它们介导谷氨酸能突触传递的钙通透性成分，并在学习、记忆和认知以及神经疾病中发挥重要作用。EU1622-14 增加激动剂的效力和通道开放概率，减慢受体失活速度，并降低单通道电导和钙通透性。这种化学探针的独特功能选择性揭示了一种增强 NMDAR 功能的机制，同时限制了过量的钙内流，表明变构调节剂可以作为离子通道通透性的偏态调节剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/e91e4b599cd6/nihms-1545792-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/ebe6ac7cb358/nihms-1545792-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/4723c51e2db2/nihms-1545792-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/9b198e1dcc08/nihms-1545792-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/ab1cfdbf6861/nihms-1545792-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/ba5c8c4bc9af/nihms-1545792-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/e91e4b599cd6/nihms-1545792-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/ebe6ac7cb358/nihms-1545792-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/4723c51e2db2/nihms-1545792-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/9b198e1dcc08/nihms-1545792-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/ab1cfdbf6861/nihms-1545792-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/ba5c8c4bc9af/nihms-1545792-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cae/6986806/e91e4b599cd6/nihms-1545792-f0006.jpg

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