Alternative splicing of GluN1 gates glycine-primed internalization of NMDA receptors
Bibliographic record
Abstract
Summary N-methyl-D-aspartate receptors (NMDARs), a principal subtype of excitatory neurotransmitter receptor, are composed as tetrameric assemblies of two glycine-binding GluN1 subunits and two glutamate-binding GluN2 subunits. Gating of the NMDARs requires binding of four co-agonist molecules, but the receptors can signal non-ionotropically through binding of glycine, alone, to its cognate site on GluN1. A consequence of this signalling by glycine is that NMDARs are primed such that subsequent gating, produced by glycine and glutamate, drives receptor internalization. The GluN1 subunit is not a singular molecular species in the CNS, rather there are 8 alternatively spliced isoforms of this subunit produced by including or excluding the N1 and the C1, C2 or C2’ polypeptide cassettes. Whether alternative splicing affects glycine priming signalling is unknown. Here, using recombinant NMDARs expressed heterologously we discovered that glycine priming of NMDARs critically depends on alternative splicing: the four splice isoforms lacking the N1 cassette, encoded in exon 5, are primed by glycine whereas glycine priming is blocked in the four splice variants containing the N1 cassette. On the other hand, the C-terminal cassettes – C1, C2 or C2’ – had no effect on glycine priming signalling. Nor was glycine priming affected by the GluN2 subunit in the receptor. In wild-type mice we found that glycine primed internalization of synaptic NMDARs in CA1 hippocampal pyramidal neurons. With mice we engineered such that GluN1 obligatorily contained the N1 cassette, glycine did not prime synaptic NMDARs in pyramidal neurons. In contrast to pyramidal neurons, we discovered that in wild-type mice, synaptic NMDARs in CA1 inhibitory interneurons were resistant to glycine priming. But we recapitulated glycine priming in inhibitory interneurons in mice engineered such that GluN1 obligatorily lacked the N1 cassette. Our findings reveal a previously unsuspected molecular function for alternative splicing of GluN1 in controlling non-ionotropic signalling of NMDAR by glycine and the consequential cell surface dynamics of the receptors.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".