RAMPs: 5 years on, where to now?

doi:10.1016/j.tips.2003.09.001

Trends in Pharmacological Sciences

Volume 24, Issue 11, November 2003, Pages 596-601

https://doi.org/10.1016/j.tips.2003.09.001 Get rights and content

Abstract

It is now ∼5 years since the identification of the family of receptor activity modifying proteins (RAMPs). This finding revolutionized concepts of the pharmacology of G-protein-coupled receptors (GPCRs) and revealed that GPCR accessory proteins not only assist trafficking and folding but also define receptor type. Since the identification of RAMPs as modulators of the trafficking and properties of the calcitonin-receptor-like receptor, much work has focused on improving our understanding of the nature of RAMP–GPCR dimers, the extent to which they occur, and the consequence of this association. In this article, we review recent developments, including the identification of new receptor partners and novel roles for RAMPs.

Section snippets

The RAMP–receptor interface is a viable pharmacological target

There is considerable interest in the development of CGRP receptor antagonists as therapeutic agents to treat migraine [10] and, more recently, opiate-withdrawal syndromes [11]. Most small-molecule drugs that act at GPCRs interact in the transmembrane region of the receptor 2, 12. The nature of the CGRP receptor indicated that equivalent molecules that act at the CL receptor component would lack specificity between CGRP and adrenomedullin receptors. Although this is the case for some compounds

How do RAMPs interact with receptor partners?

Biochemical and confocal microscopy data indicate that RAMPs and their receptor partners form stable dimers that originate in the endoplasmic reticulum (ER) and Golgi apparatus, and are maintained during the processes of translocation to the cell surface, agonist activation, internalization and lysosomal degradation (Figure 2) 6, 16, 17, 18, 19.

Interaction with RAMPs leads to modification of the terminal glycosylation of the CL receptor 2, 18. Although thought originally to be exclusive to

The molecular basis of RAMP–receptor interaction

Initial work using chimeras between RAMP1 and RAMP2 indicated that the N-terminus of each RAMP is the principal domain involved in generating CGRP and adrenomedullin receptors, respectively, from the CL receptor [21]. Recent work shows that, in addition to modulating receptor type, this domain is sufficient to maintain the functional interaction between the RAMP and CL receptors. Expression of the extracellular domain (ECD) of RAMP1 as a chimera with the transmembrane domain of the

A role for the C-terminal domain of RAMPs

The C-terminus of each RAMP is only 10 amino acids long (Figure 1) and its role is ill defined. A recent deletion analysis of the C-terminal domain in RAMP1 indicates that it contains an ER-retention sequence (between Ser141 and Thr144) that leads to retention of the protein in the ER in the absence of receptor coexpression [23]. The functional significance of the domain for receptor function is less clear. Although C-terminal deletion has little effect on CGRP binding, one study found a

How widely do RAMPs act?

RAMPs have a relatively ubiquitous distribution, with at least one RAMP expressed in most tissues examined 2, 3, 27. This distribution extends beyond that of the characterized receptor partners, the CTR and CL receptor, which indicates a much broader role for RAMPs in receptor function. Indeed, there is widespread interest in the possibility that RAMPs act as general accessory proteins for GPCRs and that they are required for the cell-surface expression or determining the phenotype of many

Class II GPCRs and RAMPs

To date, studies of RAMP–GPCR interactions have focused predominantly on the receptors for calcitonin and its related peptides (i.e. CGRP, adrenomedullin and amylin). These receptors belong to the peptide-hormone receptor subgroup of the Class II family of GPCRs, which share several structural features [28]. Given these similarities, and the wide distribution of RAMPs, we hypothesized that RAMPs might also interact with other Class II GPCRs.

Using receptor-mediated redistribution of the

Physiological significance of the RAMP–receptor interaction

The presence of CGRP and adrenomedullin receptors is broadly paralleled by the presence of the CL receptor and RAMPs 1 and 2, respectively, in both tissues and cell lines 34, 35, 36, 37. Similarly, RAMPs and CTRs occur at sites of amylin receptor expression [5], but whether this always occurs remains to be investigated.

Although not studied directly, RAMPs also colocalize with the more recently identified receptor partners. For example, mRNA that encodes VPAC1 receptors is expressed in sites

Concluding remarks

Recent work reveals new scope for RAMP action, with new receptor partners identified and novel actions of RAMPs found. The strong interaction between specific RAMPs and receptors, in particular the VPAC1 receptor, without known functional consequence makes it likely that additional actions of RAMPs will be discovered. New data also shed light on the nature of the interface between RAMPs and their receptor partners. This provides scope for the development of novel drugs and for predicting

Acknowledgements

Patrick Sexton and Arthur Christopoulos are Senior Research Fellows of the National Health and Medical Research Council (NHMRC) of Australia. Work in our laboratories is supported by project grant numbers 990024 and 145702 from the NHMRC.

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Three RAMP subtypes (RAMP1–3) have been identified, which show about 30% homology to one another [13]. By interacting with RAMP1, CLR acquires a high affinity for calcitonin gene-related peptide (CGRP), whereas interaction with either RAMP2 or RAMP3 gives CLR a high affinity for AM [12–15]. We previously showed that homozygous AM or RAMP2 knockout (AM−/ − or RAMP2−/ −) mice die in utero due to edema and hemorrhage related to abnormal angiogenesis [16,17].
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