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Examining Mechanisms for Voltage-Sensitive Calcium Channel-Mediated Secretion Events in Bone Cells

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Abstract

In addition to their well-described functions in cell excitability, voltage-sensitive calcium channels (VSCCs) serve a critical role in calcium (Ca2+)-mediated secretion of pleiotropic paracrine and endocrine factors, including those produced in bone. Influx of Ca2+ through VSCCs activates intracellular signaling pathways to modulate a variety of cellular processes that include cell proliferation, differentiation, and bone adaptation in response to mechanical stimuli. Less well understood is the role of VSCCs in the control of bone and calcium homeostasis mediated through secreted factors. In this review, we discuss the various functions of VSCCs in skeletal cells as regulators of Ca2+ dynamics and detail how these channels might control the release of bioactive factors from bone cells. Because VSCCs are druggable, a better understanding of the multiple functions of these channels in the skeleton offers the opportunity for developing new therapies to enhance and maintain bone and to improve systemic health.

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Abbreviations

AA:

Arachidonic acid

ABC:

ATP-binding cassette

AC:

Adenylate cyclase

Akt:

Protein kinase B

ALP:

Alkaline phosphatase

ATP:

Adenosine triphosphate

BMP2:

Bone morphogenetic protein 2

BMSCs:

Bone marrow stromal cells

Ca2+ :

Calcium

CAM:

Calmodulin

CAMK:

Ca2+/calmodulin-dependent protein kinase

cAMP:

Cyclic adenosine monophosphate

CollA1:

Collagen 1α1

COX-2:

Cyclooxygenase-2

CRE:

CAMP-response elements

CREB:

CAMP-response element-binding protein

DAG:

Diacyl glycerol

Dlx5:

Distal-Less Homeobox 5

eNOS:

Endothelial nitric oxide synthase.

ER:

Endoplasmic reticulum

ERK1/2:

Extracellular signal-regulated kinases 1/2

EVs:

Extracellular vesicles

FGF23:

Fibroblast growth factor-23

FZD:

Frizzled

HPLSC:

Human periodontal ligament stem cells

IGF-I:

Insulin-like growth factor I

IP3:

Inositol-1,4,5-triphosphate

LRP5/6:

Lipoprotein receptor-related proteins 5/6

MAPK:

Mitogen-activated protein kinase

MSCF:

Macrophage colony-stimulating factor

MSCs:

Mesenchymal stem cells

mTOR:

Mammalian target of rapamycin

NFATc:

Nuclear factor of activated T cells c

NF-KB:

Nuclear factor kappa B

NO:

Nitric oxide

NSF:

N-Ethylmaleimide-sensitive factor

Ocn:

Osteocalcin

OPG:

Osteoprotegerin

Opn:

Osteopontin

Osx:

Osterix

PDGF-BB:

Platelet-derived growth factor-BB

PGE2 :

Prostaglandin E2

PI3K:

Phosphoinositide 3 kinase

PINP:

Procollagen type I N propeptide

PIP2:

Phosphatidylinositol 4,5-bisphosphate

PKA:

Protein kinase A

PKC:

Protein kinase C

PLA2:

Phospholipase A2

PLC:

Phospholipase C

PLN:

Perlecan

RANKL:

Receptor activator of nuclear factor-κB ligand

RBPs:

RIM-binding proteins

RIMs:

Rab3-interacting molecules

Runx2:

Runt-related transcription factor 2

SNAP:

Soluble NSF attachment protein

SNARE:

SNAP receptor

SYT:

Synaptotagmin

TGF-β:

Transcription growth factor superfamily β

TNFα:

Tumor necrosis factor-alpha

tSNAREs:

Target membrane SNAREs

VSCC:

Voltage-sensitive calcium channels

vSNAREs:

Vesicle membrane SNAREs

Wnt:

Wingless-related integration site

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Funding

This study was supported by 1F32AR074893-01 to CSW and 1R01AR074473-01 to WRT and MCFC.

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Authors and Affiliations

  1. Department of Physical Therapy, School of Health and Human Sciences, Indiana University, Indianapolis, IN, 46202, USA

    Perla C. Reyes Fernandez, Christian S. Wright & William R. Thompson

  2. Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, 46202, USA

    Perla C. Reyes Fernandez, Christian S. Wright & William R. Thompson

  3. Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA

    Mary C. Farach-Carson

  4. Departments of BioSciences and Bioengineering, Rice University, Houston, TX, 77005, USA

    Mary C. Farach-Carson

  5. Department of Anatomy, Cell Biology and Physiology, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA

    William R. Thompson

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Perla C. Reyes Fernandez, Christian S. Wright, Mary C. Farach-Carson, and William R. Thompson declare that there are no conflicts of interest.

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Reyes Fernandez, P.C., Wright, C.S., Farach-Carson, M.C. et al. Examining Mechanisms for Voltage-Sensitive Calcium Channel-Mediated Secretion Events in Bone Cells. Calcif Tissue Int 113, 126–142 (2023). https://doi.org/10.1007/s00223-023-01097-w

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