Gabapentin Disrupts Binding of Perlecan to the α<sub>2</sub>δ<sub>1</sub> Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation
Perla C. Reyes Fernandez,
Christian S. Wright,
Adrianna N. Masterson,
Xin Yi,
Tristen V. Tellman,
Andrei Bonteanu,
Katie Rust,
Megan L. Noonan,
Kenneth E. White,
Karl J. Lewis,
Uma Sankar,
Julia M. Hum,
Gregory Bix,
Danielle Wu,
Alexander G. Robling,
Rajesh Sardar,
Mary C. Farach-Carson,
William R. Thompson
Affiliations
Perla C. Reyes Fernandez
Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA
Christian S. Wright
Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA
Adrianna N. Masterson
Department of Chemistry and Chemical Biology, School of Science, Indiana University, Indianapolis, IN 46202, USA
Xin Yi
Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA
Tristen V. Tellman
Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
Andrei Bonteanu
Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
Katie Rust
Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA
Megan L. Noonan
Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Kenneth E. White
Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Karl J. Lewis
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
Uma Sankar
Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Julia M. Hum
Division of Biomedical Science, College of Osteopathic Medicine, Marian University, Indianapolis, IN 46222, USA
Gregory Bix
Departments of Neurosurgery and Neurology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
Danielle Wu
Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
Alexander G. Robling
Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN 46202, USA
Rajesh Sardar
Department of Chemistry and Chemical Biology, School of Science, Indiana University, Indianapolis, IN 46202, USA
Mary C. Farach-Carson
Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA
William R. Thompson
Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN 46202, USA
Our 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::α2δ1 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 α2δ1, necessary for bone force transmission and sensitive to the drug GBP.
