Effect of calcium ions on human calcitonin. Possible implications for bone resorption by osteoclasts

Calcium ions (Ca(2+)) are indispensable for life and are involved in important physiological actions, which makes maintaining a constant level of blood Ca(2+) essential. Ca(2+) is mainly stored in bones which serve as a reservoir and its homeostasis is modulated by various hormones. Human calcitonin (hCt) is a small peptide hormone that exerts its physiological effect on Ca(2+) metabolism by means of osteoclast-mediated bone resorption inhibition. Most of these actions are mediated through peptide/receptor interaction that acts via a second messenger. However, in vitro studies have shown that hCt can interact with membrane lipids to form ion channels in membrane models. This ability is due to the peptide's secondary structure and aggregation state, that can be modulated by different molecules. In our study, we evaluated the effect of Ca(2+), at different concentrations, both on the hCt ion channel incorporated into a planar lipid membrane made up of phosphatidylcholine containing 15% phosphatidylglycerol and on the secondary structure of hCt in an aqueous environment. Ca(2+) is able to interact with the hCt peptide by acting on the channel incorporated into the membrane as well as on the peptide in solution, both by increasing hCt channel frequency and in solution promoting α-helix formation, that counteracts the fibrillating process. These experimental observations, suggesting that hCt senses Ca(2+) concentration variations, strengthen the hypothesis that channel formation represents an extra source of Ca(2+) entry into osteoclasts in addition to the well-known interaction of the monomer with the specific receptor.