The expanding repertoire of receptor activity modifying protein (RAMP) function

Abstract

Receptor activity modifying proteins (RAMPs) associate with G-protein-coupled receptors (GPCRs) at the plasma membrane and together bind a variety of peptide ligands, serving as a communication interface between the extracellular and intracellular environments. The collection of RAMP-interacting GPCRs continues to expand and now consists of GPCRs from families A, B and C, suggesting that RAMP activity is extremely prevalent. RAMP association with GPCRs can regulate GPCR function by altering ligand binding, receptor trafficking and desensitization, and downstream signaling pathways. Here, we elaborate on these RAMP-dependent mechanisms of GPCR regulation, which provide opportunities for pharmacological intervention.

Keywords: CLR; G-protein; GPCR; desensitization; ligand; signaling; trafficking.

Figure 1

RAMP family phylogenetic tree. The RAMP family TreeFam (TF33386), assembled by a database of the European Bioinformatics Institute, contains 139 sequences from 53 species. Shown here is a condensed tree with a focus on model organisms and their relation to humans. Details on bioinformatic construction of this tree are provided in the literature (Guindon et al., 2010, Ruan et al., 2008). A color version of the figure is available online.

Figure 2

Effects of RAMP association on CT receptor-like receptor (CLR) and CT receptor (CTR). (A) For cell surface expression, CLR requires the presence of one of the RAMP family members. CLR associates with RAMPs in the ER, facilitating plasma membrane expression. Association with RAMP1 yields a high affinity CT gene-related peptide (CGRP) receptor, whereas CLR association with RAMP2 or -3 results in a potent adrenomedullin (AM) receptor. (B) Conversely, CTR is trafficked to the plasma membrane independent of RAMPs. In the absence of a RAMP, CTR binds CT. In association with RAMP1, -2, -3, the CTR-RAMP complex binds amylin (AMY). A color version of the figure is available online.

Figure 3

Examples of effects of RAMP association on GPCR activity. GPCR-RAMP associations may promote GPCR plasma membrane localization; ligand specificity; functional selectivity; and trafficking. Receptor chaperone and ligand specificity: RAMPs can enable GPCRs to shuttle to the plasma membrane, and differential RAMP association may dictate preference for endogenous ligands. For example, RAMP association with CT receptor-like receptor (CLR) in the endoplasmic reticulum promotes localization of CLR at the plasma membrane, where CLR-RAMP1 can bind CT gene-related peptide (CGRP), and CLR-RAMP2 or –RAMP3 can bind adrenomedullin (AM). Functional selectivity: Depending on the GPCR-RAMP association, GPCRs may preferentially couple to certain G-proteins, such as G_s, G_q, and G_i, or other non-G-proteins, such as β-arrestin. For example, corticotrophin releasing factor receptor-1 (CRF1R)-RAMP2 preferentially couples to G_i/o/t/z and G_q/11. Receptor trafficking: GPCR-RAMP associations may affect whether the GPCR is degraded or recycled back to the plasma membrane following internalization. For example, RAMP3 contains a PSD-95/Discs-large/ZO-1 (PDZ) domain that interacts with N-ethylmaleimide-sensitive factor (NSF) to shunt CLR away from the degradative pathway it enters following internalization when associated with RAMP1 or RAMP2. ?: Other effects of GPCR-RAMP associations remain to be discovered. A color version of the figure is available online.