Article ; Online: Biased modulators of NMDA receptors control channel opening and ion selectivity.
2020 Volume 16, Issue 2, Page(s) 188–196
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 ( ... ...
| 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. |
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| MeSH term(s) | Allosteric Regulation/drug effects ; Animals ; Calcium/metabolism ; Cells, Cultured ; Female ; Glutamic Acid/metabolism ; Glutamic Acid/pharmacology ; Glycine/metabolism ; Glycine/pharmacology ; HEK293 Cells ; High-Throughput Screening Assays/methods ; Humans ; Ion Channel Gating/drug effects ; Mice, Inbred C57BL ; Neurons/drug effects ; Neurons/metabolism ; Oocytes/drug effects ; Oocytes/physiology ; Pyrrolidines/pharmacology ; Receptors, N-Methyl-D-Aspartate/agonists ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/metabolism ; Xenopus laevis | ||||||||||
| Chemical Substances | NR2B NMDA receptor ; Pyrrolidines ; Receptors, N-Methyl-D-Aspartate ; Glutamic Acid (3KX376GY7L) ; Calcium (SY7Q814VUP) ; Glycine (TE7660XO1C) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2020-01-20 | ||||||||||
| Publishing country | United States | ||||||||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 2202962-X | ||||||||||
| ISSN | 1552-4469 ; 1552-4450 | ||||||||||
| ISSN (online) | 1552-4469 | ||||||||||
| ISSN | 1552-4450 | ||||||||||
| DOI | 10.1038/s41589-019-0449-5 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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