Ca<sup>2+</sup>‐dependent induction of TRPM2 currents in hippocampal neurons
Bibliographic record
Abstract
TRPM2 is a Ca(2+)-permeable member of the transient receptor potential melastatin family of cation channels whose activation by reactive oxygen/nitrogen species (ROS/RNS) and ADP-ribose (ADPR) is linked to cell death. While these channels are broadly expressed in the CNS, the presence of TRPM2 in neurons remains controversial and more specifically, whether they are expressed in neurons of the hippocampus is an open question. With this in mind, we examined whether functional TRPM2 channels are expressed in this neuronal population. Using a combination of molecular and biochemical approaches, we demonstrated the expression of TRPM2 transcripts and proteins in hippocampal pyramidal neurons. Whole-cell voltage-clamp recordings were subsequently carried out to assess the presence of TRPM2-mediated currents. Application of hydrogen peroxide or peroxynitrite to cultured hippocampal pyramidal neurons activated an inward current that was abolished upon removal of extracellular Ca(2+), a hallmark of TRPM2 activation. When ADPR (300 microM) was included in the patch pipette, a large inward current developed but only when depolarizing voltage ramps were continuously (1/10 s) applied to the membrane. This current exhibited a linear current-voltage relationship and was sensitive to block by TRPM2 antagonists (i.e. clotrimazole, flufenamic acid and N-(p-amylcinnamoyl)anthranilic acid (ACA)). The inductive effect of voltage ramps on the ADPR-dependent current required voltage-dependent Ca(2+) channels (VDCCs) and a rise in [Ca(2+)](i). Consistent with the need for a rise in [Ca(2+)](i), activation of NMDA receptors (NMDARs), which are highly permeable to Ca(2+), was also permissive for current development. Importantly, given the prominent vulnerability of CA1 neurons to free-radical-induced cell death, we confirmed that, with ADPR in the pipette, a brief application of NMDA could evoke a large inward current in CA1 pyramidal neurons from hippocampal slices that was abolished by the removal of extracellular Ca(2+), consistent with TRPM2 activation. Such a current was absent in interneurons of CA1 stratum radiatum. Finally, infection of cultured hippocampal neurons with a TRPM2-specific short hairpin RNA (shRNA(TRPM2)) significantly reduced both the expression of TRPM2 and the amplitude of the ADPR-dependent current. Taken together, these results indicate that hippocampal pyramidal neurons possess functional TRPM2 channels whose activation by ADPR is functionally coupled to VDCCs and NMDARs through a rise in [Ca(2+)](i).
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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 | 0.001 |
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".