NMDA receptors require multiple pre-opening gating steps for efficient synaptic activity
| Autor: | Johansen B. Amin, Noele Certain, Miaomiao He, Lonnie P. Wollmuth, Aaron Gochman |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular 0301 basic medicine Nervous system Agonist medicine.drug_class Glutamic Acid Gating Neurotransmission Receptors N-Methyl-D-Aspartate Synaptic Transmission 03 medical and health sciences 0302 clinical medicine medicine Humans Ion channel Chemistry General Neuroscience Glutamate receptor Transmembrane protein HEK293 Cells 030104 developmental biology medicine.anatomical_structure Synapses Helix Biophysics NMDA receptor Ion Channel Gating Neuroscience 030217 neurology & neurosurgery |
| DOI: | 10.1101/2020.06.09.142687 |
| Popis: | NMDA receptors (NMDAR) are glutamate-gated ion channels that mediate the majority of fast excitatory synaptic transmission in the nervous system. A central feature of NMDAR physiology is the opening of the ion channel driven by presynaptically-released glutamate. Using glutamate applications to outside-out patches containing a single NMDAR in the continuous presence of the co-agonist glycine, we find that agonist-bound receptors transition to the open state via two conformations, an ‘unconstrained pre-active’ state that can rapidly transition to the open state and contributes to synaptic events, and a ‘constrained pre-active’ state that requires more energy and hence time to open and does not contribute to fast signaling. To define how agonist binding might drive these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for the GluN1 and GluN2A subunits. Displacements of the central pore-forming M3 segments define the energy of fast channel opening. However, to enter the unconstrained conformation and contribute to fast signaling, a peripheral helix, the GluN2 pre-M1, must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of another nearby peripheral element, the GluN1 and GluN2A S2-M4. We conclude that peripheral structural elements – pre-M1 and S2-M4 – work in concert to remove constraints and prime the channel for rapid opening, thus facilitating fast synaptic transmission. |
| Databáze: | OpenAIRE |
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