RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor

Abstract

Calcitonin-gene-related peptide (CGRP) and adrenomedullin are related peptides with distinct pharmacological profiles. Here we show that a receptor with seven transmembrane domains, the calcitonin-receptor-like receptor (CRLR), can function as either a CGRP receptor or an adrenomedullin receptor, depending on which members of a new family of single-transmembrane-domain proteins, which we have called receptor-activity-modifying proteins or RAMPs, are expressed. RAMPs are required to transport CRLR to the plasma membrane. RAMP1 presents the receptor at the cell surface as a mature glycoprotein and a CGRP receptor. RAMP2-transported receptors are core-glycosylated and are adrenomedullin receptors.

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Figure 1
Figure 2: Xenopus oocytes expressing RAMP1 show large and dose-dependent responses to CGRP.
Figure 3: Expression of RAMP1 with CRLR in oocytes and HEK293T cells.
Figure 4: RAMP1 and CRLR are localized together on the cell surface when they are co-expressed.
Figure 5: RAMP1 acts to increase the relative molecular mass of CRLR at the same time as specific binding to 125I-labelled CGRP1 becomes apparent.
Figure 6: Amino-acid sequences of human RAMPs 1, 2 and 3, aligned for comparison.
Figure 7: A northern blot analysis of mRNA encoding RAMPs 1, 2 and 3 in cell lines and tissues.
Figure 8: Expression of RAMP2 plus CRLR in oocytes and in HEK293T cells.
Figure 9

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Acknowledgements

We thank D. Cousens for probing the MTN blots; E. Murrison for help with cloningRAMP2; S. Brown for isolation of the CRLR/RAMP1 cell lines; J. M. Rommens and L. C. Tsui for CFTR; W. Born and J. Fischer for CRLR and for discussions; and members of the RSU for their support.

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Correspondence to Steven M. Foord.

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McLatchie, L., Fraser, N., Main, M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339 (1998). https://doi.org/10.1038/30666

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