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Distinct Receptor Activity-Modifying Protein Domains Differentially Modulate Interaction with Calcitonin Receptors

Department of Pharmacology, Monash University, Victoria, Australia (P.M.S., A.C., G.C., N.T.); and Howard Florey Institute (P.M.S., M.U., A.A.) and Department of Pharmacology (A.C., M.U.), the University of Melbourne, Victoria, Australia

Calcitonin receptors (CTRs) dimerize with receptor activity-modifying proteins (RAMPs) to generate high-affinity amylin (AMY) receptors; however, the relative contribution of individual RAMP domains to the formation of AMY receptors is poorly understood. We have used chimeras between RAMP1 and RAMP2 that specifically exchanged the N-terminal, transmembrane, or C-terminal domain and examined these in assays of [¹²⁵I]amylin binding or peptide-induced cAMP signaling in COS-7 cells transiently transfected with wild-type or chimeric RAMPs and human CTRa. The specificity of peptides in competition for [¹²⁵I]amylin binding was principally dictated by the N-terminal domain present in the chimeras; however, the maximal level of binding induced was dictated by the transmembrane domain present. This extended previous data (Zumpe et al., 2000) to provide a distinction between the transmembrane domain and the C terminus in this function. In contrast to the effects on binding, each of the RAMP domains played a role in the signaling phenotype of the receptors. In particular, the potency of calcitonin gene-related peptide (CGRP) was most influenced by the C-terminal domain present, in which the presence of the RAMP1 C-terminal domain led to increased potency over CTRa alone, whereas chimeras with the RAMP2 C-terminal domain did not induce increased CGRP potency. The data provide additional support for the importance of the N terminus in determining binding affinity but reveal a prominent role of the transmembrane domain in the strength of amylin binding and a unique role for the C terminus in signaling by peptides to stimulate cAMP production.

Received for publication December 21, 2005.

Accepted for publication March 10, 2006.

Address correspondence to: Dr. Patrick M. Sexton, Department of Pharmacology, Building 13E, Monash University, Clayton, 3800, Victoria, Australia. E-mail: patrick.sexton{at}med.monash.edu.au

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