Evidence for calcitonin receptor heterogeneity: binding studies with nonhelical analogs.
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.
Nakamuta
H
H
Department of Pharmacology, Faculty of Pharmaceutical Science, Setsunan University, Osaka, Japan.
Orlowski
R C
RC
Epand
R M
RM
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001862:Bone Resorption; D001921:Brain / Q000378:metabolism; D002116:Calcitonin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000378:metabolism; D008297:Male; D010010:Osteoclasts / Q000502:physiology / Q000648:ultrastructure; D011487:Protein Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface / Q000378:metabolism*
D018003:Receptors, Calcitonin; D011956:Receptors, Cell Surface; C064775:calcitonin, salmon, Gly(8)-Ala(16)-des-Leu(19)-; C028815:salmon calcitonin; D002116:Calcitonin