ArticleProceedings of the National Academy of Sciences of the United States of America2015
Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed.
- The role of zinc homeostasis in major depressive disorder: heterogeneous pathological mechanisms and therapeutic implications.Annals of medicine · 2026Review
- Article
- Synaptic zinc plasticity shapes adaptive and maladaptive cortical plasticity following cochlear injury.Science advances · 2026Article
- Nanomolar Cadmium Disrupts Neurotransmitter Release Timing via a ROS-dependent Mechanism at the Mouse Neuromuscular Junction: Modulation by Nanomolar ZnNeurochemical research · 2026Article
- ZIP-ZnT1 complexes mediate a local ZnCellular and molecular life sciences : CMLS · 2026Article
- Context-dependent NMDA receptor dysfunction predicts seizure treatment in mice with human GluN1 variant.iScience · 2026Article
- Exogenous nanomolar zinc ion (ZnBiometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2025Article
- Article
- The Astrocytic Zinc Transporter ZIP12 Is a Synaptic Protein That Contributes to Synaptic Zinc Levels in the Mouse Auditory Cortex.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- The zinc receptor, ZnR/GPR39, modulates taste sensitivity by regulating ion secretion in mouse salivary gland.iScience · 2025Article
- Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor.Pharmaceuticals (Basel, Switzerland) · 2025Review
- The role of redox-active iron, copper, manganese, and redox-inactive zinc in toxicity, oxidative stress, and human diseases.EXCLI journal · 2025Review
- SLC30 (ZnT) and SLC39 (ZIP) zinc transporter families: from gatekeepers of zinc homeostasis to promoters of tumorigenesis and targets for clinical therapy.Frontiers in immunology · 2025Review
- Cryo-EM structure of the zinc-activated channel (ZAC) in the Cys-loop receptor superfamily.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- On the genesis and unique functions of zinc neuromodulation.Journal of neurophysiology · 2024Review
- Cell-type-specific enhancement of deviance detection by synaptic zinc in the mouse auditory cortex.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Trans-synaptic Association of Vesicular Zinc Transporter 3 and Shank3 Supports Synapse-Specific Dendritic Spine Structure and Function in the Mouse Auditory Cortex.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- The physiological and pathophysiological roles of copper in the nervous system.The European journal of neuroscience · 2024Review
- Cortical Zinc Signaling Is Necessary for Changes in Mouse Pupil Diameter That Are Evoked by Background Sounds with Different Contrasts.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors.
Funding
Abstract
Many excitatory synapses contain high levels of mobile zinc within glutamatergic vesicles. Although synaptic zinc and glutamate are coreleased, it is controversial whether zinc diffuses away from the release site or whether it remains bound to presynaptic membranes or proteins after its release. To study zinc transmission and quantify zinc levels, we required a high-affinity rapid zinc chelator as well as an extracellular ratiometric fluorescent zinc sensor. We demonstrate that tricine, considered a preferred chelator for studying the role of synaptic zinc, is unable to efficiently prevent zinc from binding low-nanomolar zinc-binding sites, such as the high-affinity zinc-binding site found in NMDA receptors (NMDARs). Here, we used ZX1, which has a 1 nM zinc dissociation constant and second-order rate constant for binding zinc that is 200-fold higher than those for tricine and CaEDTA. We find that synaptic zinc is phasically released during action potentials. In response to short trains of presynaptic stimulation, synaptic zinc diffuses beyond the synaptic cleft where it inhibits extrasynaptic NMDARs. During higher rates of presynaptic stimulation, released glutamate activates additional extrasynaptic NMDARs that are not reached by synaptically released zinc, but which are inhibited by ambient, tonic levels of nonsynaptic zinc. By performing a ratiometric evaluation of extracellular zinc levels in the dorsal cochlear nucleus, we determined the tonic zinc levels to be low nanomolar. These results demonstrate a physiological role for endogenous synaptic as well as tonic zinc in inhibiting extrasynaptic NMDARs and thereby fine tuning neuronal excitability and signaling.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.