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Ligand Binding and Activation of the CGRP Receptor

  • James Barwell
  • John Simms
  • Alex Conner
  • Debbie Hay
  • Mark Wheatley
  • David PoynerEmail author
Chapter

Abstract

The CGRP receptor is an atypical G-protein coupled receptor (GPCR), consisting of at least three proteins; a Family-B GPCR (calcitonin receptor-like receptor; CLR or CRLR), receptor activity modifying protein 1 (RAMP1) and receptor component protein (RCP). The extracellular domain of RAMP1 is tri-helical and possibly interacts with the extreme N-terminus of CLR to form the functional receptor. CGRP binding probably follows a two-step model of activation. The C-terminus of CGRP interacts with the N-terminus of the CLR/RAMP1 complex and its N-terminus interacts with the extracellular loops and of CLR to cause activation. The second and third extracellular loops are particularly important. During receptor activation TM helices 3 and 6 probably move apart. P343 in TM 6 is particularly important; E233 in TM3 and R173 and/or H178 in TM2 may form intermolecular interactions that may mirror the function of the DRY motif found in Family A GPCRs. Upon receptor activation the intracellular loops move to create a Gs-protein binding pocket.

Keywords

RAMP1 Family B GPCR • receptor activation molecular modelling Site-directed mutagenesis alanine scan CGRP binding 

Abbreviations

GPCR

G-protein coupled receptor

NMR

Nuclear magnetic resonance

CLR

calcitonin receptor-like receptor

RAMP1

receptor activity modifying protein

RCP

receptor component protein

CGRP

calcitonin gene related peptide

ICL

intracellular loop

ECL

extracellular loop

ECD

extracellular domain

TM

transmembrane

CRF-R2β

corticotrophin releasing factor- Receptor 2β

PACAP

pituitary adenylate cyclase-activating polypeptide

PAC1-Rs

pituitary adenylate cyclase 1- Receptor short

SCR

short consensus repeat

AMY

amylin

AM

adrenomedullin

BRET

bioluminescence resonance energy transfer

BiFC

bimolecular fluorescence complementation

GIPR

gastric inhibitory polypeptide receptor

GLP-1R

glucagon-like peptide-1 receptor

Notes

Acknowledgements

This work was supported by grants to DRP from the British Heart Foundation (studentship FS/05/054 to JB), the Wellcome Trust and the BBSRC.

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Copyright information

© Springer Science+Business Media B.V 2010

Authors and Affiliations

  • James Barwell
    • 1
  • John Simms
    • 2
  • Alex Conner
    • 3
  • Debbie Hay
    • 4
  • Mark Wheatley
    • 5
  • David Poyner
    • 1
    Email author
  1. 1.School of Life and Health SciencesAston UniversityBirminghamUK
  2. 2.Department of PharmacologyUniversity of MonashClaytonAustralia
  3. 3.Warwick Medical SchoolWarwick UniversityCoventryUSA
  4. 4.School of Biological SciencesUniversity of AucklandAucklandNew Zealand
  5. 5.School of BiosciencesBirmingham UniversityBirminghamUK

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