Regulation of NMDAR function by tyrosine phosphorylation: the role of extracellular zinc and identification of the tyrosine phosphatase step as an endogenous regulator of NMDAR activity
Bibliographic record
Abstract
The NMDA subtype of glutamate receptor is a principal mediator of excitatory synaptic transmission within the CNS. Proper NMDA receptor (NMDAR) function is crucial for normal CNS processes, while dysfunction of NMDARs can lead to a host of nervous system disorders. NMDAR function is dynamically tuned to the state of the neuron by intracellular biochemical processes, including tyrosine phosphorylation/dephosphorylation. The tyrosine kinase Src physically associates with the NMDAR complex and enhances NMDAR activity. The work outlined herein addresses two aspects of NMDAR modulation by tyrosine phosphorylation: (1) the nature of the mechanism by which Src modulates NMDARs, and (2) the identity of the phosphotyrosine phosphatase (PTP) that counteracts Src regulation of NMDARs. With recombinant receptors comprised of NR1-1a/NR2A orNR1-1a/2B subunits Src reduces voltage-independent Zn2+ inhibition. Thereby the function of recombinant NMDA receptors is potentiated by Src only when the Zn2+ levels cause tonic inhibition. In the first study of this thesis we investigated whether Src-induced potentiation of NMDARs in neurons proceeds via relief of Zn2+ inhibition. Whereas chelating extracellular Zn2+ blocked Src-induced potentiation of NR1-1a/2A receptors, Zn2+ chelation did not affect potentiation of NMDAR currents by Src applied into hippocampal neurons. Moreover, Src did not alter the Zn 2+ concentration-inhibition relationship for NMDAR currents. In dorsal horn neurons, chelating extracellular Zn2+ failed to prevent regulation of NMDA single-channel activity by endogenous Src and did not affect Src-mediated regulation of synaptic NMDARs. Thus Src potentiation of NMDAR currents is not mediated by reducing Zn2+ inhibition in hippocampal and dorsal horn neurons. In the second study presented in this thesis we show that striatal enriched tyrosine phosphatase (STEP) is a component of the NMDAR complex. Functionally, exogenous STEP depressed NMDAR single-channel activity. STEP also depressed NMDAR-mediated synaptic currents whereas inhibiting endogenous STEP enhanced these currents. In hippocampal slices administering STEP into CA1 neurons did not affect basal glutamatergic transmission but prevented LTP induction. Conversely, inhibiting STEP enhanced transmission and occluded LTP induction through an NMDAR-, Src-, and Ca2+-dependent mechanism. Thus, STEP opposes Src to regulate NMDAR activity thereby acting as a tonic brake on synaptic transmission.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".