Effect of pH-variation on insertion and ion channel formation of human calcitonin into planar lipid bilayers

Human calcitonin is the physiological hormone involved in calcium-phosphorus homeostasis. However, its use is limited by its propensity to form aggregates. We find that the type of host lipid has a pronounced influence on human calcitonin fibrillation or incorporation, as assessed by channel formation, in planar lipid membranes at neutral pH. At pH 7, human calcitonin is able to interact and form channels with negatively charged dioleoyl-phosphatidylglycerol (DOPG) bilayers and with zwitterionic palmitoyl-oleoyl phosphatidylcholine (POPC) bilayers containing 15% negatively-charged DOPG, but not with POPC bilayers. At low pH (4.5 and 3.8), the conformational variation of the peptide enables it to insert into POPC and POPC: DOPG but not into DOPG bilayers. The model proposed for human calcitonin interaction and channel formation at acidic pH was based on theoretical predictions of the protonation-deprotonation state of some aminoacids, in particular in the fibrillating sequence of peptide molecules; the length of the a-helix, and the electrostatic and/or hydrophobic interaction also seem to be relevant. These results may suggest that human calcitonin at low local pH could be involved in osteoclasts' calcium-sensitive permeability through channel formation and/or receptor interaction.