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Research ArticleArticle

A Critical Role for the Short Intracellular C Terminus in Receptor Activity-Modifying Protein Function

Madhara Udawela, George Christopoulos, Maria Morfis, Arthur Christopoulos, Siying Ye, Nanda Tilakaratne and Patrick M. Sexton
Molecular Pharmacology November 2006, 70 (5) 1750-1760; DOI: https://doi.org/10.1124/mol.106.024257
Madhara Udawela
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George Christopoulos
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Maria Morfis
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Arthur Christopoulos
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Siying Ye
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Nanda Tilakaratne
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Patrick M. Sexton
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Abstract

Receptor activity-modifying proteins (RAMPs) interact with and modify the behavior of the calcitonin receptor (CTR) and calcitonin receptor-like receptor (CLR). We have examined the contribution of the short intracellular C terminus, using constructs that delete the last eight amino acids of each RAMP. C-Terminal deletion of individual RAMPs had little effect on the signaling profile induced when complexed with CLR in COS-7 or human embryonic kidney (HEK)293 cells. Likewise, confocal microscopy revealed each of the mutant RAMPs translocated hemagglutinin-tagged CLR to the cell surface. In contrast, a pronounced effect of RAMP C-terminal truncation was seen for RAMP/CTRa complexes, studied in COS-7 cells, with significant attenuation of amylin receptor phenotype induction that was stronger for RAMP1 and -2 than RAMP3. The loss of amylin binding upon C-terminal deletion could be partially recovered with overexpression of Gαs, suggesting an impact of the RAMP C terminus on coupling of G proteins to the receptor complex. In HEK293 cells the c-Myc-RAMP1 C-terminal deletion mutant showed high receptor-independent cell surface expression; however, this construct showed low cell surface expression when expressed alone in COS-7 cells, indicating interaction of RAMPs with other cellular components via the C terminus. This mutant also had reduced cell surface expression when coexpressed with CTR. Thus, this study reveals important functionality of the RAMP C-terminal domain and identifies key differences in the role of the RAMP C terminus for CTR versus CLR-based receptors.

Footnotes

  • This work was supported by National Health and Medical Research Council (NHMRC) grant 299810 and the Ian Potter Neuropeptide laboratory. P.M.S. is a Principal Research Fellow of the NHMRC of Australia. A.C. is a Senior Research Fellow of the NHMRC.

  • M.U., G.C., and M.M. contributed equally to this work.

  • ABBREVIATIONS: Δ, deletion mutant; GPCR, G protein-coupled receptor; RAMP, receptor activity-modifying protein; CT, calcitonin; CTR, calcitonin receptor; CLR, calcitonin receptor-like receptor; AMY, amylin receptor phenotype; AM, adrenomedullin; CGRP, calcitonin gene-related peptide; CHO, Chinese hamster ovary; PDZ, postsynaptic density-95/Discs-large/ZO-1 homology; h, human; sCT, salmon calcitonin; rAmy, rat amylin; HA, hemagglutinin; WT, wild-type; DMEM, Dulbecco's modified Eagle's medium; Gpp(NH)p, guanosine 5′-(β,γ-imido)triphosphate; PBS, phosphate-buffered saline; RCP, receptor component protein.

    • Received March 9, 2006.
    • Accepted August 15, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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Research ArticleArticle

A Critical Role for the Short Intracellular C Terminus in Receptor Activity-Modifying Protein Function

Madhara Udawela, George Christopoulos, Maria Morfis, Arthur Christopoulos, Siying Ye, Nanda Tilakaratne and Patrick M. Sexton
Molecular Pharmacology November 1, 2006, 70 (5) 1750-1760; DOI: https://doi.org/10.1124/mol.106.024257

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Research ArticleArticle

A Critical Role for the Short Intracellular C Terminus in Receptor Activity-Modifying Protein Function

Madhara Udawela, George Christopoulos, Maria Morfis, Arthur Christopoulos, Siying Ye, Nanda Tilakaratne and Patrick M. Sexton
Molecular Pharmacology November 1, 2006, 70 (5) 1750-1760; DOI: https://doi.org/10.1124/mol.106.024257
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