T-Type voltage-sensitive calcium channels mediate mechanically-induced intracellular calcium oscillations in osteocytes by regulating endoplasmic reticulum calcium dynamics.
One of the earliest responses of bone cells to mechanical stimuli is a rise in intracellular calcium (Ca(2+)), and osteocytes in particular exhibit robust oscillations in Ca(2+) when subjected to loading. Previous studies implicate roles for both the endoplasmic reticulum (ER) and T-Type voltage-sensitive calcium channels (VSCC) in these responses, but their interactions or relative contributions have not been studied. By observing Ca(2+) dynamics in the cytosol (Ca(2+)cyt) and the ER (Ca(2+)ER), the focus of this study was to explore the role of the ER and T-Type channels in Ca(2+) signaling in bone cells. We demonstrate that inhibition of T-Type VSCC in osteocytes significantly reduces the number of Ca(2+)cyt responses and affects Ca(2+)ER depletion dynamics. Simultaneous observation of Ca(2+) exchange among these spaces revealed high synchrony between rises in Ca(2+)cyt and depressions in Ca(2+)ER, and this synchrony was significantly reduced by challenging T-Type VSCC. We further confirmed that this effect was mediated directly through the ER and not through store-operated Ca(2+) entry (SOCE) pathways. Taken together, our data suggests that T-Type VSCC facilitate the recovery of Ca(2+)ER in osteocytes to sustain mechanically-induced Ca(2+) oscillations, uncovering a new mechanism underlying the behavior of osteocytes as mechanosensors.
Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Genevieve N
GN
Brown
Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Pui L
PL
Leong
Bone Bioengineering Laboratory, Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Electronic address: ed.guo@columbia.edu.
X Edward
XE
Guo
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism*; D049990:Membrane Transport Modulators / Q000494:pharmacology; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
D020747:Calcium Channels, T-Type; D049990:Membrane Transport Modulators; D002118:Calcium
Calcium; Endoplasmic reticulum; Fluid flow; Osteocytes; Voltage-sensitive calcium channels