Activity-dependent development of P2X7 current and Ca2+ entry in rabbit osteoclasts
L N Naemsch1, S J Dixon, S M Sims
1Canadian Institutes of Health Research Group in Skeletal Development and Remodeling, Department of Physiology and Division of Oral Biology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario N6A 5C1, Canada.
The Journal of Biological Chemistry
|August 10, 2001
Summary
High concentrations of adenosine triphosphate (ATP) activate P2X(7) receptors in osteoclasts, providing the first evidence of an extracellular ligand-gated calcium influx pathway. This mechanism may inhibit bone resorption stimulated by mechanical forces.
Area of Science:
- Cell biology
- Physiology
- Biochemistry
Background:
- Bone remodeling involves local factors and mechanical stimuli.
- Mechanical stress releases adenosine triphosphate (ATP), affecting osteoclast activity.
- High ATP concentrations can inhibit osteoclastic resorption, but the mechanism was unclear.
Purpose of the Study:
- To investigate if osteoclasts express P2X(7) receptors.
- To determine the function of P2X(7) receptors in osteoclasts.
- To elucidate the role of ATP in mechanical modulation of bone remodeling.
Main Methods:
- Patch clamp electrophysiology on rabbit osteoclasts.
- Application of P2X(7) receptor agonists (BzATP, ATP) and antagonists (PPADS).
- Measurement of intracellular calcium ([Ca(2+)](i)) changes and ion flux.
Main Results:
- High ATP/BzATP activated a slowly deactivating inward current in osteoclasts.
- The channel was permeable to small cations, not forming pores.
- BzATP induced extracellular calcium-dependent [Ca(2+)](i) elevations, inhibited by PPADS.
- P2X(7) receptor expression was confirmed in rat osteoclasts via immunocytochemistry.
Conclusions:
- Osteoclasts express functional P2X(7) receptors.
- High ATP concentrations activate P2X(7) receptors, leading to calcium influx.
- This pathway represents a novel mechanism for mechanical stimuli to inhibit osteoclastic bone resorption.
Related Concept Videos
01:31Osteoclasts in Bone Remodeling
Osteoclasts are cells responsible for bone resorption and remodeling. They originate from hematopoietic progenitor cells present in the bone marrow. Numerous progenitor cells fuse to form multinucleated cells, each with 10-20 nuclei. A single osteoclast has a diameter of 150 to 200 µM. These cells have ruffled borders that break down the underlying bone tissue and release minerals such as calcium into the blood in bone resorption. Osteoclasts cling to bones with their ruffled edges during bone...
01:27Feedback Regulation of Calcium Concentration
Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
01:16Calmodulin-dependent Signaling
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
01:17Hormones and Bone Tissue
The endocrine system produces and secretes hormones, which interact with the skeletal system. These hormones control bone growth, maintain bone once it is formed, and remodel it.
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...
Hormones That Influence Osteoblasts and/or Maintain the Matrix
Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth. This happens in several ways: first, it triggers chondrocyte...