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

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dc.citation.articleNumber1857en_US
dc.citation.issueNumber12en_US
dc.citation.journalTitleBiomoleculesen_US
dc.citation.volumeNumber12en_US
dc.contributor.authorReyes Fernandez, Perla C.en_US
dc.contributor.authorWright, Christian S.en_US
dc.contributor.authorMasterson, Adrianna N.en_US
dc.contributor.authorYi, Xinen_US
dc.contributor.authorTellman, Tristen V.en_US
dc.contributor.authorBonteanu, Andreien_US
dc.contributor.authorRust, Katieen_US
dc.contributor.authorNoonan, Megan L.en_US
dc.contributor.authorWhite, Kenneth E.en_US
dc.contributor.authorLewis, Karl J.en_US
dc.contributor.authorSankar, Umaen_US
dc.contributor.authorHum, Julia M.en_US
dc.contributor.authorBix, Gregoryen_US
dc.contributor.authorWu, Danielleen_US
dc.contributor.authorRobling, Alexander G.en_US
dc.contributor.authorSardar, Rajeshen_US
dc.contributor.authorFarach-Carson, Mary C.en_US
dc.contributor.authorThompson, William R.en_US
dc.date.accessioned2023-01-27T14:47:20Zen_US
dc.date.available2023-01-27T14:47:20Zen_US
dc.date.issued2022en_US
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 PLNen_US
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.en_US
dc.identifier.digitalbiomolecules-12-01857en_US
dc.identifier.doihttps://doi.org/10.3390/biom12121857en_US
dc.identifier.urihttps://hdl.handle.net/1911/114270en_US
dc.language.isoengen_US
dc.publisherMDPIen_US
dc.rightsThis article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) licenseen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleGabapentin Disrupts Binding of Perlecan to the α2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensationen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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