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Molecular Pharmacology

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Research ArticleArticle

Multiple Amylin Receptors Arise from Receptor Activity-Modifying Protein Interaction with the Calcitonin Receptor Gene Product

George Christopoulos, Katie J. Perry, Maria Morfis, Nanda Tilakaratne, Yongyi Gao, Neil J. Fraser, Martin J. Main, Steven M. Foord and Patrick M. Sexton
Molecular Pharmacology July 1999, 56 (1) 235-242; DOI: https://doi.org/10.1124/mol.56.1.235
George Christopoulos
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Katie J. Perry
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Maria Morfis
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Nanda Tilakaratne
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Yongyi Gao
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Neil J. Fraser
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Martin J. Main
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Steven M. Foord
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Patrick M. Sexton
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Abstract

Receptor activity-modifying proteins (RAMPs) are single-transmembrane proteins that transport the calcitonin receptor-like receptor (CRLR) to the cell surface. RAMP 1-transported CRLR is a calcitonin gene-related peptide (CGRP) receptor. RAMP 2- or RAMP 3-transported CRLR is an adrenomedullin receptor. The role of RAMPs beyond their interaction with CRLR, a class II G protein-coupled receptor, is unclear. In this study, we have examined the role of RAMPs in generating amylin receptor phenotypes from the calcitonin (CT) receptor gene product. Cotransfection of RAMP 1 or RAMP 3 with the human CT receptor lacking the 16-amino acid insert in intracellular domain 1 (hCTRI1−) into COS-7 cells induced specific125I-labeled rat amylin binding. RAMP 2 or vector cotransfection did not cause significant increases in specific amylin binding. Competition-binding characterization of the RAMP-induced amylin receptors revealed two distinct phenotypes. The RAMP 1-derived amylin receptor demonstrated the highest affinity for salmon CT (IC50, 3.01 ± 1.44 × 10−10 M), a high to moderate affinity for rat amylin (IC50, 7.86 ± 4.49 × 10−9 M) and human CGRPα (IC50, 2.09 ± 1.63 × 10−8 M), and a low affinity for human CT (IC50, 4.47 ± 0.78 × 10−7 M). In contrast, whereas affinities for amylin and the CTs were similar for the RAMP 3-derived receptor, the efficacy of human CGRPα was markedly reduced (IC50, 1.12 ± 0.45 × 10−7 M; P < .05 versus RAMP 1). Functional cyclic AMP responses in COS-7 cells cotransfected with individual RAMPs and hCTRI1− were reflective of the phenotypes seen in competition for amylin binding. Confocal microscopic localization of c-myc-tagged RAMP 1 indicated that, when transfected alone, RAMP 1 almost exclusively was located intracellularly. Cotransfection with calcitonin receptor (CTR)I1− induced cell surface expression of RAMP 1. The results of experiments cross-linking 125I-labeled amylin to RAMP 1/hCTR-transfected cells with bis succidimidyl suberate were suggestive of a cell-surface association of RAMP 1 and the receptors. Our data suggest that in the CT family of receptors, and potentially in other class II G protein-coupled receptors, the cellular phenotype is likely to be dynamic in regard to the level and combination of both the receptor and the RAMP proteins.

Footnotes

    • Received April 14, 1999.
    • Accepted May 18, 1999.
  • Send reprint requests to: Dr. Patrick M. Sexton, Department of Pharmacology, University of Melbourne, Parkville 3052, Victoria, Australia. E-mail:p.sexton{at}pharmacology.unimelb.edu.au

  • This work was funded in part by the National Health and Medical Research Council of Australia and by GlaxoWellcome, Australia. P.M.S. is a Research Fellow of the National Health and Medical Research Council of Australia.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (1)
Molecular Pharmacology
Vol. 56, Issue 1
1 Jul 1999
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Research ArticleArticle

Multiple Amylin Receptors Arise from Receptor Activity-Modifying Protein Interaction with the Calcitonin Receptor Gene Product

George Christopoulos, Katie J. Perry, Maria Morfis, Nanda Tilakaratne, Yongyi Gao, Neil J. Fraser, Martin J. Main, Steven M. Foord and Patrick M. Sexton
Molecular Pharmacology July 1, 1999, 56 (1) 235-242; DOI: https://doi.org/10.1124/mol.56.1.235

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Research ArticleArticle

Multiple Amylin Receptors Arise from Receptor Activity-Modifying Protein Interaction with the Calcitonin Receptor Gene Product

George Christopoulos, Katie J. Perry, Maria Morfis, Nanda Tilakaratne, Yongyi Gao, Neil J. Fraser, Martin J. Main, Steven M. Foord and Patrick M. Sexton
Molecular Pharmacology July 1, 1999, 56 (1) 235-242; DOI: https://doi.org/10.1124/mol.56.1.235
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