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ORIGINAL ARTICLE

Pharmacological Discrimination of Calcitonin Receptor: Receptor Activity-Modifying Protein Complexes

School of Biological Sciences, University of Auckland, Auckland, New Zealand (D.L.H.); Howard Florey Institute (G.C., P.M.S.) and Department of Pharmacology (A.C.), University of Melbourne, Victoria, Australia; and School of Life and Health Sciences, Aston University, Birmingham, United Kingdom (D.R.P.)

Abstract

Calcitonin (CT) receptors dimerize with receptor activity-modifying proteins (RAMPs) to create high-affinity amylin (AMY) receptors, but there is no reliable means of pharmacologically distinguishing these receptors. We used agonists and antagonists to define their pharmacology, expressing the CT_(a) receptor alone or with RAMPs in COS-7 cells and measuring cAMP accumulation. Intermedin short, otherwise known as adrenomedullin 2, mirrored the action of CGRP, being a weak agonist at CT_(a), AMY_2(a), and AMY_3(a) receptors but considerably more potent at AMY_1(a) receptors. Likewise, the linear calcitonin gene-related peptide (CGRP) analogs (Cys(ACM)^2,7)hCGRP and (Cys(Et)^2,7)hCGRP were only effective at AMY_1(a) receptors, but they were partial agonists. As previously observed in COS-7 cells, there was little induction of the AMY_2(a) receptor phenotype; thus, AMY_2(a) was not examined further in this study. The antagonist peptide salmon calcitonin_8-32 (sCT_8-32) did not discriminate strongly between CT and AMY receptors; however, AC187 was a more effective antagonist of AMY responses at AMY receptors, and AC413 additionally showed modest selectivity for AMY_1(a) over AMY_3(a) receptors. CGRP_8-37 also demonstrated receptor-dependent effects. CGRP_8-37 more effectively antagonized AMY at AMY_1(a) than AMY_3(a) receptors, although it was only a weak antagonist of both, but it did not inhibit responses at the CT_(a) receptor. Low CGRP_8-37 affinity and agonism by linear CGRP analogs at AMY_1(a) are the classic signature of a CGRP₂ receptor. Our data indicate that careful use of combinations of agonists and antagonists may allow pharmacological discrimination of CT_(a), AMY_1(a), and AMY_3(a) receptors, providing a means to delineate the physiological significance of these receptors.

Address correspondence to: Dr. Patrick M. Sexton, Howard Florey Institute, University of Melbourne, Victoria 3010, Australia. E-mail: p.sexton{at}hfi.unimelb.edu.au

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