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

Fernandez, Perla C Reyes; Wright, Christian S; Masterson, Adrianna N.; Yi, Xin; Tellman, Tristen V.; Bonteanu, Andrei; Rust, Katie; Noonan, Megan L.; White, Kenneth E.; Lewis, Karl J.; Sankar, Uma; Hum, Julia M.; Bix, Gregory; Wu, Danielle; Robling, Alexander G.; Sardar, Rajesh; Farach-Carson, Mary C.; Thompson, William R.

doi:10.3390/biom12121857

Cited by 6 publications

(3 citation statements)

References 91 publications

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“…The α 2 domain interacts with extracellular matrix molecules 49 and soluble ligands 50 in several cell types, including neurons and muscle. Further, we recently showed that α 2 δ 1 binds tightly to perlecan (PLN), 51 a large extracellular matrix heparan sulfate proteoglycan. Perlecan deficiency alters lacunocanalicular structure, 5 results in fewer tethering elements within the lacunocanalicular system, 26 , 52 and impairs skeletal mechanosensation.…”

Section: Discussionmentioning

confidence: 99%

Loss of the auxiliary α2δ1 voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading

Kelly,

Sharma,

Wright

et al. 2024

JBMR Plus

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Voltage sensitive calcium channels (VSCCs) influence bone structure and function, including anabolic responses to mechanical loading. While the pore-forming (α1) subunit of VSCCs allows Ca2+ influx, auxiliary subunits regulate the biophysical properties of the pore. The α2δ1 subunit influences gating kinetics of the α1 pore and enables mechanically induced signaling in osteocytes; however, the skeletal function of α2δ1 in vivo remains unknown. In this work, we examined the skeletal consequences of deleting Cacna2d1, the gene encoding α2δ1. Dual energy X-ray absorptiometry (DEXA) and microcomputed tomography (μCT) imaging demonstrated that deletion of α2δ1 diminished bone mineral content and density in both male and female C57BL/6 mice. Structural differences manifested in both trabecular and cortical bone for males, while the absence of α2δ1 affected only cortical bone in female mice. Deletion of α2δ1 impaired skeletal mechanical properties in both sexes, as measured by three-point bending to failure. While no changes in osteoblast number or activity were found for either sex, male mice displayed a significant increase in osteoclast number, accompanied by increased eroded bone surface and upregulation of genes that regulate osteoclast differentiation. Deletion of α2δ1 also rendered the skeleton insensitive to exogenous mechanical loading in males. While previous work demonstrates that VSCCs are essential for anabolic responses to mechanical loading, the mechanism by which these channels sense and respond to force remained unclear. Our data demonstrate that the α2δ1 auxiliary VSCC subunit functions to maintain baseline bone mass and strength through regulation of osteoclast activity, and also provides skeletal mechanotransduction in male mice. These data reveal a molecular player in our understanding of the mechanisms by which VSCCs influence skeletal adaptation.

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Section: Discussionmentioning

confidence: 99%

Loss of the auxiliary α2δ1 voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading

Kelly,

Sharma,

Wright

et al. 2024

JBMR Plus

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“…Voltage-gated calcium channels (VSCCs) often contain α2δ subunits that interact directly with the ECM. 49,102 Ectodomains of ion channels may be held in scaffold by PGs such as perlecan. 50 Transient receptor potential channels are nonselective cation channels that are involved in various mechanosensitive processes 103 including osmosensation, cardiovascular, and respiratory functions.…”

Section: Integrinsmentioning

confidence: 99%

“…As a group, these channels are present in the plasma membranes of cells and can open or close in response to ionic gradients, membrane deformation, nucleotide or ligand activation, or mechanosensitive complex activation. Voltage‐gated calcium channels (VSCCs) often contain α2δ subunits that interact directly with the ECM 49,102 . Ectodomains of ion channels may be held in scaffold by PGs such as perlecan 50 .…”

Section: Introductionmentioning

confidence: 99%

Proteoglycans in mechanobiology of tissues and organs: Normal functions and mechanopathology

Farach‐Carson,

Wu,

França

2024

Proteoglycan Research

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Proteoglycans (PGs) are a diverse class of glycoconjugates that serve critical functions in normal mechanobiology and mechanopathology. Both the protein cores and attached glycosaminoglycan (GAG) chains function in mechanically sensitive processes, and loss of either can contribute to development of pathological conditions. PGs function as key components of the extracellular matrix (ECM), where they can serve as mechanosensors in mechanosensitive tissues including bone, cartilage, tendon, blood vessels, and soft organs. The mechanical properties of these tissues depend on the presence and function of PGs, which play important roles in tissue elasticity, osmolarity, and pressure sensing, and response to physical activity. Tissue responses depend on cell surface mechanoreceptors that include integrins, CD44, voltage‐sensitive ion channels, transient receptor potential, and piezo channels. PGs contribute to cell and molecular interplay in wound healing, fibrosis, and cancer, where they transduce the mechanical properties of the ECM and influence the progression of various context‐specific conditions and diseases. The PGs that are most important in mechanobiology vary depending on the tissue and its functions and functional needs. Perlecan, for example, is important in the mechanobiology of basement membranes, cardiac muscle, and skeletal muscle, while aggrecan plays a primary role in the mechanical properties of cartilage and joints. A variety of techniques have been used to study the mechanobiology of PGs, including atomic force microscopy, mouse knockout models, and in vitro cell culture experiments with three‐dimensional organoid models. These studies have helped to elucidate the tissue‐specific roles that PGs play in cell‐level mechanosensing and tissue mechanics. Overall, the study of PGs in mechanobiology is yielding fundamental new concepts in the molecular basis of mechanosensing that can open the door to the development of new treatments for a host of conditions related to mechanopathology.

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Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

Mongiat,

Pascal,

Poletto

et al. 2024

Proteoglycan Research

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Antiangiogenic therapy is an established method for the treatment of several cancers and vascular‐related diseases. Most of the agents employed target the vascular endothelial growth factor A, the major cytokine stimulating angiogenesis. However, the efficacy of these treatments is limited by the onset of drug resistance. Therefore, it is of fundamental importance to better understand the mechanisms that regulate angiogenesis and the microenvironmental cues that play significant role and influence patient treatment and outcome. In this context, here we review the importance of the three basement membrane (BM) heparan sulfate proteoglycans (HSPGs), namely perlecan, agrin, and collagen XVIII. These HSPGs are abundantly expressed in the vasculature and, due to their complex molecular architecture, they interact with multiple endothelial cell receptors, deeply affecting their function. Under normal conditions, these proteoglycans exert proangiogenic functions. However, in pathological conditions such as cancer and inflammation, extracellular matrix remodeling leads to the degradation of these large precursor molecules and the liberation of bioactive processed fragments displaying potent angiostatic activity. These unexpected functions have been demonstrated for the C‐terminal fragments of perlecan and collagen XVIII, endorepellin, and endostatin. These bioactive fragments can also induce autophagy in vascular endothelial cells which contributes to angiostasis. Overall, BM proteoglycans deeply affect angiogenesis counterbalancing proangiogenic signals during tumor progression and represent possible means to develop new prognostic biomarkers and novel therapeutic approaches for the treatment of solid tumors.

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

Cited by 6 publications

References 91 publications

Loss of the auxiliary α2δ1 voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading

Loss of the auxiliary α2δ1 voltage-sensitive calcium channel subunit impairs bone formation and anabolic responses to mechanical loading

Proteoglycans in mechanobiology of tissues and organs: Normal functions and mechanopathology

Proteoglycans of basement membranes: Crucial controllers of angiogenesis, neurogenesis, and autophagy

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