Negatively charged residues in the first extracellular loop of the L-type CaV1.2 channel anchor the interaction with the CaVα2δ1 auxiliary subunit
Bibliographic record
Abstract
Voltage-gated L-type Ca V 1.2 channels in cardiomyocytes exist as heteromeric complexes. Co-expression of Ca V α2δ1 with Ca V β/Ca V α1 proteins reconstitutes the functional properties of native L-type currents, but the interacting domains at the Ca V 1.2/Ca V α2δ1 interface are unknown. Here, a homology-based model of Ca V 1.2 identified protein interfaces between the extracellular domain of Ca V α2δ1 and the extracellular loops of the Ca V α1 protein in repeats I (IS1S2 and IS5S6), II (IIS5S6), and III (IIIS5S6). Insertion of a 9-residue hemagglutinin epitope in IS1S2, but not in IS5S6 or in IIS5S6, prevented the co-immunoprecipitation of Ca V 1.2 with Ca V α2δ1. IS1S2 contains a cluster of three conserved negatively charged residues Glu-179, Asp-180, and Asp-181 that could contribute to non-bonded interactions with Ca V α2δ1. Substitutions of Ca V 1.2 Asp-181 impaired the co-immunoprecipitation of Ca V β/Ca V 1.2 with Ca V α2δ1 and the Ca V α2δ1-dependent shift in voltage-dependent activation gating. In contrast, single substitutions in Ca V 1.2 in neighboring positions in the same loop (179, 180, and 182–184) did not significantly alter the functional up-regulation of Ca V 1.2 whole-cell currents. However, a negatively charged residue at position 180 was necessary to convey the Ca V α2δ1-mediated shift in the activation gating. We also found a more modest contribution from the positively charged Arg-1119 in the extracellular pore region in repeat III of Ca V 1.2. We conclude that Ca V 1.2 Asp-181 anchors the physical interaction that facilitates the Ca V α2δ1-mediated functional modulation of Ca V 1.2 currents. By stabilizing the first extracellular loop of Ca V 1.2, Ca V α2δ1 may up-regulate currents by promoting conformations of the voltage sensor that are associated with the channel's open state.
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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) | 0.004 | 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".