The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Pharmacological disruption of calcium channel trafficking by the α 2 δ ligand gabapentin
Open accessAbstract
The mechanism of action of the antiepileptic and antinociceptive drugs of the gabapentinoid family has remained poorly understood. Gabapentin (GBP) binds to an exofacial epitope of the α 2 δ-1 and α 2 δ-2 auxiliary subunits of voltage-gated calcium channels, but acute inhibition of calcium currents by GBP is either very minor or absent. We formulated the hypothesis that GBP impairs the ability of α 2 δ subunits to enhance voltage-gated Ca 2+ channel plasma membrane density by means of an effect on trafficking. Our results conclusively demonstrate that GBP inhibits calcium currents, mimicking a lack of α 2 δ only when applied chronically, but not acutely, both in heterologous expression systems and in dorsal root-ganglion neurons. GBP acts primarily at an intracellular location, requiring uptake, because the effect of chronically applied GBP is blocked by an inhibitor of the system-L neutral amino acid transporters and enhanced by coexpression of a transporter. However, it is mediated by α 2 δ subunits, being prevented by mutations in either α 2 δ-1 or α 2 δ-2 that abolish GBP binding, and is not observed for α 2 δ-3, which does not bind GBP. Furthermore, the trafficking of α 2 δ-2 and Ca V 2 channels is disrupted both by GBP and by the mutation in α 2 δ-2, which prevents GBP binding, and we find that GBP reduces cell-surface expression of α 2 δ-2 and Ca V 2.1 subunits. Our evidence indicates that GBP may act chronically by displacing an endogenous ligand that is normally a positive modulator of α 2 δ subunit function, thereby impairing the trafficking function of the α 2 δ subunits to which it binds.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Structure and Regulation of Voltage-Gated Ca 2+ Channels
Catterall, W. A. (2000) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.16.1.521 · Cited by 2,344
The Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the α2δ Subunit of a Calcium Channel
Gee, N. S., Brown, J. P., Dissanayake, V. U. K., Offord, J., Thurlow, R., & Woodruff, G. N. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.10.5768 · Cited by 1,181
Whittaker, C. A., & Hynes, R. O. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-05-0259 · Cited by 753
Field, M. J., Cox, P. J., Stott, E., Melrose, H., Offord, J., Su, T.-Z., Bramwell, S., Corradini, L., England, S., Winks, J., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409066103 · Cited by 591
Self-citationTaylor, C. P., Angelotti, T., & Fauman, E. (2007) · Epilepsy Research · doi:10.1016/j.eplepsyres.2006.09.008 · Cited by 565
Auxiliary subunits: essential components of the voltage-gated calcium channel complex
Arikkath, J., & Campbell, K. P. (2003) · Current Opinion in Neurobiology · doi:10.1016/s0959-4388(03)00066-7 · Cited by 505
β Subunits of Voltage-Gated Calcium Channels
Dolphin, A. C. (2003) · Journal of Bioenergetics and Biomembranes · doi:10.1023/b:jobb.0000008026.37790.5a · Cited by 423
Self-citationFunctional biology of the α2δ subunits of voltage-gated calcium channels
Davies, A., Hendrich, J., Van Minh, A. T., Wratten, J., Douglas, L., & Dolphin, A. C. (2007) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2007.03.005 · Cited by 360
Self-citationFehrenbacher, J. C., Taylor, C. P., & Vasko, M. R. (2003) · Pain · doi:10.1016/s0304-3959(03)00173-8 · Cited by 336
Calcium channel α2δ1 subunit mediates spinal hyperexcitability in pain modulation
Li, C.-Y., Zhang, X.-L., Matthews, E. A., Li, K.-W., Kurwa, A., Boroujerdi, A., Gross, J., Gold, M. S., Dickenson, A. H., Feng, G., et al. (2006) · Pain · doi:10.1016/j.pain.2006.04.022 · Cited by 273
Cited by
Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage
Costigan, M., Scholz, J., & Woolf, C. J. (2009) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.051508.135531 · Cited by 2,025
Mechanisms of action of currently used antiseizure drugs
Sills, G. J., & Rogawski, M. A. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.107966 · Cited by 489
Calcium channel auxiliary α2δ and β subunits: trafficking and one step beyond
Dolphin, A. C. (2012) · Nature Reviews Neuroscience · doi:10.1038/nrn3311 · Cited by 368
Self-citationAntidepressants and gabapentinoids in neuropathic pain: Mechanistic insights
Kremer, M., Salvat, E., Muller, A., Yalcin, I., & Barrot, M. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.06.057 · Cited by 312
Chen, J., Li, L., Chen, S.-R., Chen, H., Xie, J.-D., Sirrieh, R. E., MacLean, D. M., Zhang, Y., Zhou, M.-H., Jayaraman, V., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.02.021 · Cited by 283
Metadata
- Authors
- Hendrich, J., Van Minh, A. T., Heblich, F., Nieto-Rostro, M., Watschinger, K., Striessnig, J., Wratten, J., Davies, A., & Dolphin, A. C.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2008-03-04
- Volume
- 105
- Issue
- 9
- Pages
- 3628-3633
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2122304769
- Cited by
- 417
- References
- 32
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- green
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
How to cite
Cite CoChat for the checks on this page, and the paper for its own findings.
- This page
- CoChat. (2026). Citation check: Pharmacological disruption of calcium channel trafficking by the α 2 δ ligand gabapentin. https://app.cochat.ai/papers/10.1073/pnas.0708930105
- The paper
- Hendrich, J., Van Minh, A. T., Heblich, F., Nieto-Rostro, M., Watschinger, K., Striessnig, J., Wratten, J., Davies, A., & Dolphin, A. C. (2008). Pharmacological disruption of calcium channel trafficking by the α 2 δ ligand gabapentin. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0708930105
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
