Accessory proteins that regulate GPCR expression pharmacology and localization

7.6.1 RAMPs

GPCRs are monomeric, seven transmembrane spanning proteins, the majority of which are easily expressed in heterologous expression systems. However, a small subset of GPCRs exist that are resistant to expression and/or activation. The reason for this resistance was unclear until recently when new studies identified a family of accessory proteins that are necessary for the expression of some GPCRs, RAMPS (receptor activity modifying proteins) (Fig. 7.1d). RAMPs are predicted to exert their effects on receptor expression in three ways: they transport receptors to the surface ofthe plasma membrane, they define the pharmacology ofreceptors, and they determine the glycosylation state of receptors (for review, see Foord SM 1999). For example, the calcitonin receptor-like receptors (CRLRs) require the coexpression of RAMP1,2, or 3 to yield CGRP-, adrenomedullin-, or amylin-activated receptors, respectively (Buhlmann et al. 1999; McLatchie LM 1998; Muff et al. 1999). Structural studies reveal that the N-terminal domain of RAMPs is the critical determinant for both the glycosylation state and the ligand-binding site of CRLRs (Fraser et al. 1999). In addition, RAMP1 directly interacts with the receptor and defines the ligand recognition sites (Leuthauser et al. 2000). While studies on the role of RAMPs in regulating receptor expression have mainly been directed at the calcitonin family of receptors, RAMP mRNAs are very widely expressed thus their role in regulating the expression of other GPCRs remains to be determined. For example, mGluR7 is a GPCR curiously resistant to expression and/or activation in heterologous expression systems (Okamoto et al. 1994; Saugstad et al. 1994) and thus may require the coexpression of a RAMP for optimal activation.

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