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First published online 9 December 2008
doi: 10.1242/jcs.031534

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Activation of P2X7 receptors causes isoform-specific translocation of protein kinase C in osteoclasts

CIHR Group in Skeletal Development and Remodeling, and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1

^* Author for correspondence (e-mail: stephen.sims{at}schulich.uwo.ca)

Accepted 27 September 2008

Nucleotides, released in response to mechanical or inflammatory stimuli, signal through P2 nucleotide receptors in many cell types. Osteoclasts express P2X7 receptors (encoded by P2rx7) – Ca²⁺-permeable channels that are activated by high concentrations of extracellular ATP. Genetic disruption of P2rx7 leads to increased resorption and reduced skeletal response to mechanical stimuli. To investigate whether P2X7 receptors couple to activation of protein kinase C (PKC), RAW 264.7 cells were differentiated into multinucleated osteoclast-like cells and live-cell confocal imaging was used to localize enhanced green fluorescent protein (EGFP)-tagged PKC. Benzoylbenzoyl-ATP (BzATP; a P2X7 agonist) induced transient translocation of PKC to the basolateral membrane. UTP or ATP (10 µM), which activate P2 receptors other than P2X7, failed to induce translocation. Moreover, BzATP failed to induce PKC translocation in osteoclasts derived from the bone marrow of P2rx7^–/– mice, demonstrating specificity for P2X7. BzATP induced a transient rise of cytosolic Ca²⁺, and removal of extracellular Ca²⁺ abolished the translocation of PKC that was induced by BzATP (but not by phorbol ester). We examined the isoform specificity of this response, and observed translocation of the Ca²⁺-dependent isoforms PKC and PKCβI, but not the Ca²⁺-independent isoform PKC. Thus, activation of P2X7 receptors specifically induces Ca²⁺-dependent translocation of PKC to the basolateral membrane domain of osteoclasts, an aspect of spatiotemporal signaling not previously recognized.

Key words: Bone resorption, Cytosolic Ca²⁺, Green fluorescent protein, PKC, PKCβI, PKC, P2 purinoceptor

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