{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:05:19Z","timestamp":1791518719205,"version":"4.3.4"},"reference-count":87,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1R01AR074473-01"],"award-info":[{"award-number":["1R01AR074473-01"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["UL1 TR001108"],"award-info":[{"award-number":["UL1 TR001108"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1F32AR074893-01"],"award-info":[{"award-number":["1F32AR074893-01"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["1R01AR074473-01"],"award-info":[{"award-number":["1R01AR074473-01"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1 TR001108"],"award-info":[{"award-number":["UL1 TR001108"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["1F32AR074893-01"],"award-info":[{"award-number":["1F32AR074893-01"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1R01AR074473-01"],"award-info":[{"award-number":["1R01AR074473-01"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["UL1 TR001108"],"award-info":[{"award-number":["UL1 TR001108"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1F32AR074893-01"],"award-info":[{"award-number":["1F32AR074893-01"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Faculty Research Development funds through Marian University","award":["1R01AR074473-01"],"award-info":[{"award-number":["1R01AR074473-01"]}]},{"name":"Faculty Research Development funds through Marian University","award":["UL1 TR001108"],"award-info":[{"award-number":["UL1 TR001108"]}]},{"name":"Faculty Research Development funds through Marian University","award":["1F32AR074893-01"],"award-info":[{"award-number":["1F32AR074893-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified \u201ctethering elements\u201d (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 \u03b12\u03b41 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and \u03b12\u03b41 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between \u03b12\u03b41 and PLN domains and demonstrated for the first time that \u03b12\u03b41 strongly associates with PLN via its domain III. Furthermore, \u03b12\u03b41 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::\u03b12\u03b41 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and \u03b12\u03b41, necessary for bone force transmission and sensitive to the drug GBP.<\/jats:p>","DOI":"10.3390\/biom12121857","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T05:42:00Z","timestamp":1670823720000},"page":"1857","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Gabapentin Disrupts Binding of Perlecan to the \u03b12\u03b41 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9408-4222","authenticated-orcid":false,"given":"Perla C.","family":"Reyes Fernandez","sequence":"first","affiliation":[{"name":"Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9594-2759","authenticated-orcid":false,"given":"Christian S.","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianna N.","family":"Masterson","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, School of Science, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristen V.","family":"Tellman","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Bonteanu","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"Department of Bioengineering, George R. Brown School of Engineering, Rice University, Houston, TX 77005, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7460-7508","authenticated-orcid":false,"given":"Katie","family":"Rust","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan L.","family":"Noonan","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth E.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl J.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uma","family":"Sankar","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4703-7428","authenticated-orcid":false,"given":"Julia M.","family":"Hum","sequence":"additional","affiliation":[{"name":"Division of Biomedical Science, College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Bix","sequence":"additional","affiliation":[{"name":"Departments of Neurosurgery and Neurology, School of Medicine, Tulane University, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3386-8239","authenticated-orcid":false,"given":"Danielle","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"Department of Bioengineering, George R. Brown School of Engineering, Rice University, Houston, TX 77005, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander G.","family":"Robling","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9680-1301","authenticated-orcid":false,"given":"Rajesh","family":"Sardar","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Chemical Biology, School of Science, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4526-3088","authenticated-orcid":false,"given":"Mary C.","family":"Farach-Carson","sequence":"additional","affiliation":[{"name":"Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA"},{"name":"Department of Bioengineering, George R. Brown School of Engineering, Rice University, Houston, TX 77005, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7022-585X","authenticated-orcid":false,"given":"William R.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA"},{"name":"Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA"},{"name":"Division of Biomedical Science, College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/jbmr.320","article-title":"The amazing osteocyte","volume":"26","author":"Bonewald","year":"2011","journal-title":"J. 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