Gabapentin Disrupts Binding of Perlecan to the α 2δ1 Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation

Authors

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

Publication Date

12-12-2022

Journal

Biomolecules

Abstract

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.

Keywords

perlecan, voltage-sensitive calcium channels, α2δ1, gabapentin, mechanosensation, bone, osteocytes

Comments

Supplementary Materials

PMID: 36551284