Binding of the nonhelical salmon calcitonin (sCT) analog, [Gly8,Ala16]-des-Leu19-sCT to membrane preparations from rat brain could be analyzed in terms of two independent binding sites. The high and low affinity binding sites for this analog were named CT-L (L, linear) and CT-H (H, helix), respectively. Although the CT-H type receptor has a low affinity for the nonhelical analogs, it binds the helical sCT with high affinity and therefore represents a CT binding site. The physiological significance for the existence of subtypes of specific CT receptors is not clear. The [Gly8,Ala16]-des-Leu19-sCT suppressed the osteoclastic bone resorption in tissue culture at low concentration (0.1 nM). The dose of [Gly8,Ala16]-des-Leu19-sCT required for this hypocalcemic activity was highly correlated with the binding affinity of this analog to the CT-L receptor subtype. In addition, human CT interacted with the CT-L type receptor at about 100th the concentration of that required for the displacement of sCT. We conclude that binding to the CT-L type receptor is required for hypocalcemic activity in mammals.