Gabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation

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dc.citation.articleNumber1857
dc.citation.issueNumber12
dc.citation.journalTitleBiomolecules
dc.citation.volumeNumber12
dc.contributor.authorReyes Fernandez, Perla C.
dc.contributor.authorWright, Christian S.
dc.contributor.authorMasterson, Adrianna N.
dc.contributor.authorYi, Xin
dc.contributor.authorTellman, Tristen V.
dc.contributor.authorBonteanu, Andrei
dc.contributor.authorRust, Katie
dc.contributor.authorNoonan, Megan L.
dc.contributor.authorWhite, Kenneth E.
dc.contributor.authorLewis, Karl J.
dc.contributor.authorSankar, Uma
dc.contributor.authorHum, Julia M.
dc.contributor.authorBix, Gregory
dc.contributor.authorWu, Danielle
dc.contributor.authorRobling, Alexander G.
dc.contributor.authorSardar, Rajesh
dc.contributor.authorFarach-Carson, Mary C.
dc.contributor.authorThompson, William R.
dc.date.accessioned2023-01-27T14:47:20Z
dc.date.available2023-01-27T14:47:20Z
dc.date.issued2022
dc.description.abstractOur understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified “tethering elements” (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN
dc.identifier.citationReyes Fernandez, Perla C., Wright, Christian S., Masterson, Adrianna N., et al.. "Gabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation." <i>Biomolecules,</i> 12, no. 12 (2022) MDPI: https://doi.org/10.3390/biom12121857.
dc.identifier.digitalbiomolecules-12-01857
dc.identifier.doihttps://doi.org/10.3390/biom12121857
dc.identifier.urihttps://hdl.handle.net/1911/114270
dc.language.isoeng
dc.publisherMDPI
dc.rightsThis article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleGabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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