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A High-throughput Calcium-flux Assay to Study NMDA-receptors with Sensitivity to Glycine/D-serine and Glutamate
Published on: July 10, 2018
Zinc effects on NMDA receptor gating kinetics.
Stacy A Amico-Ruvio1, Swetha E Murthy, Thomas P Smith
1Department of Biochemistry, University at Buffalo, Buffalo, New York, USA.
Biophysical Journal
|April 21, 2011
Summary
Zinc modulates neuronal excitability by affecting NMDA receptor channels. This study reveals zinc binding increases channel opening energy barriers, impacting synaptic plasticity.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Zinc is present in synaptic vesicles of forebrain glutamatergic neurons.
- Zinc influences neuronal excitability and synaptic plasticity via poorly understood mechanisms.
- Zinc directly inhibits NMDA-sensitive glutamate-gated channels through high-affinity and low-affinity binding.
Purpose of the Study:
- To investigate the high-affinity allosteric effect of zinc on NMDA receptor gating kinetics.
- To examine the impact of nanomolar zinc concentrations on block-resistant NMDA receptors.
- To develop a kinetic model for zinc's effect on NMDA receptor function.
Main Methods:
- Examined gating kinetics of individual block-resistant NMDA receptors using nanomolar zinc concentrations.
- Performed kinetic modeling based on observed changes in channel open probability, closure, and burst durations.
- Tested the model's predictive power for macroscopic responses and synaptic currents.
Main Results:
- Block-insensitive NMDA receptors showed lower intrinsic open probabilities but remained sensitive to zinc inhibition.
- Zinc binding led to longer channel closures and shorter openings within bursts, without affecting interburst intervals.
- Kinetic modeling indicated that zinc binding increases opening energy barriers and destabilizes open states.
Conclusions:
- Zinc binding to NMDA receptors increases the energy barrier for channel opening and reduces the stability of open states.
- The developed kinetic model accurately predicts zinc-dependent changes in macroscopic NMDA receptor currents.
- This research provides mechanistic insight into how nanomolar zinc concentrations modulate synaptic transmission via 2A-type NMDA receptors.
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