Dataset Information

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

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.

SUBMITTER: Reyes Fernandez PC

PROVIDER: S-EPMC9776037 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Gabapentin Disrupts Binding of Perlecan to the α<sub>2</sub>δ<sub>1</sub> Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation.

Reyes Fernandez Perla C PC Wright Christian S CS Masterson Adrianna N AN Yi Xin X Tellman Tristen V TV Bonteanu Andrei A Rust Katie K Noonan Megan L ML White Kenneth E KE Lewis Karl J KJ Sankar Uma U Hum Julia M JM Bix Gregory G Wu Danielle D Robling Alexander G AG Sardar Rajesh R Farach-Carson Mary C MC Thompson William R WR

Biomolecules 20221212 12

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 ...[more]

PMID: 36551284

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Project description:BackgroundMuscle wasting is a debilitating co-morbidity affecting most advanced cancer patients. Alongside enhanced muscle catabolism, defects in muscle repair/regeneration contribute to cancer-associated wasting. Among the factors implicated in suppression of muscle regeneration are cytokines that interfere with myogenic signal transduction pathways. Less understood is how other cancer/wasting-associated cues, such as metabolites, contribute to muscle dysfunction. This study investigates how the metabolite succinate affects myogenesis and muscle regeneration.MethodsWe leveraged an established ectopic metabolite treatment (cell permeable dimethyl-succinate) strategy to evaluate the ability of intracellular succinate elevation to 1) affect myoblast homeostasis (proliferation, apoptosis), 2) disrupt protein dynamics and induce wasting-associated atrophy, and 3) modulate in vitro myogenesis. In vivo succinate supplementation experiments (2% succinate, 1% sucrose vehicle) were used to corroborate and extend in vitro observations. Metabolic profiling and functional metabolic studies were then performed to investigate the impact of succinate elevation on mitochondria function.ResultsWe found that in vitro succinate supplementation elevated intracellular succinate about 2-fold, and did not have an impact on proliferation or apoptosis of C2C12 myoblasts. Elevated succinate had minor effects on protein homeostasis (~25% decrease in protein synthesis assessed by OPP staining), and no significant effect on myotube atrophy. Succinate elevation interfered with in vitro myoblast differentiation, characterized by significant decreases in late markers of myogenesis and fewer nuclei per myosin heavy chain positive structure (assessed by immunofluorescence staining). While mice orally administered succinate did not exhibit changes in overall body composition or whole muscle weights, these mice displayed smaller muscle myofiber diameters (~6% decrease in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distribution), which was exacerbated when muscle regeneration was induced with barium chloride injury. Significant decreases in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distributions were observed 7 days and 28 days post injury. Elevated numbers of myogenin positive cells (3-fold increase) supportive of the differentiation defects observed in vitro were observed 28 days post injury. Metabolic profiling and functional metabolic assessment of myoblasts revealed that succinate elevation caused both widespread metabolic changes and significantly lowered maximal cellular respiration (~35% decrease).ConclusionsThis study broadens the repertoire of wasting-associated factors that can directly modulate muscle progenitor cell function and strengthens the hypothesis that metabolic derangements are significant contributors to impaired muscle regeneration, an important aspect of cancer-associated muscle wasting.

Dataset Information

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

Publications

Gabapentin Disrupts Binding of Perlecan to the α<sub>2</sub>δ<sub>1</sub> Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation.

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

Publications

Gabapentin Disrupts Binding of Perlecan to the α<sub>2</sub>δ<sub>1</sub> Voltage Sensitive Calcium Channel Subunit and Impairs Skeletal Mechanosensation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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