Regulation of extracellular calcium sensing in rat osteoclasts by femtomolar calcitonin concentrations

Certain eukaryotic cells can sense changes in their extracellular Ca²⁺ concentration through molecular structures termed Ca²⁺sensing receptors (CaRs). We have shown recently that in the bone-resorbing osteoclast, a unique cell surface-expressed ryanodine receptor (RyR), functions as the CaR. The present study demonstrates that the sensitivity of this receptor is modulated by physiological femtomolar concentrations of the bone-conserving hormone, calcitonin. Calcitonin was found to inhibit cytosolic Ca²⁺ responses to both Ca²⁺ and Ni²⁺. The latter inhibition was mimicked by amylin (10^-12 M), calcitonin gene-related peptide (10^-12 M), cholera toxin (5 μg/l), and dibutyryl adenosine 3′, 5′-cyclicmonophosphate (cAMP) (2.5 × 10^-4 or 5 × 10^-4 M) and was reversed by the protein kinase A phosphorylation inhibitor, IP-20. Finally, using a quench flow module, we showed that cellular cAMP levels rise to a peak within 25 ms of calcitonin application; this is consistent with the peptide's rapid effect on CaR activation. We conclude, therefore, that cAMP plays a critical role in the control of CaR function by calcitonin. calcium ion channel; bone resorption; osteoporosis; ryanodine receptor.