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 recept ors (CaRs). We have shown recently that in the bone-resorbing osteocla st, a unique cell surface-expressed ryanodine receptor (RyR), function s as the CaR. The present study demonstrates that the sensitivity of t his receptor is modulated by physiological femtomolar concentrations o f the bone-conserving hormone, calcitonin. Calcitonin was found to inh ibit cytosolic Ca2+ responses to both Ca2+ and Ni2+. The latter inhibi tion was mimicked by amylin (10(-12) M), calcitonin gene-related pepti de (10(-12) M), cholera toxin (5 mu g/l), and dibutyryl adenosine 3',5 '-cyclic monophosphate (cAMP) (2.5 x 10(-4) or 5 x 10(-4) M) and was r eversed by the protein kinase A phosphorylation inhibitor, IP-20. Fina lly, using a quench flow module, we showed that cellular cAMP levels r ise to a peak within 25 ms of calcitonin application; this is consiste nt with the peptide's rapid effect on CaR activation. We conclude, the refore, that cAMP plays a critical role in the control of CaR function by calcitonin.