Ligand Binding and Activation of the CGRP Receptor

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


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.


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



G-protein coupled receptor


Nuclear magnetic resonance


calcitonin receptor-like receptor


receptor activity modifying protein


receptor component protein


calcitonin gene related peptide


intracellular loop


extracellular loop


extracellular domain




corticotrophin releasing factor- Receptor 2β


pituitary adenylate cyclase-activating polypeptide


pituitary adenylate cyclase 1- Receptor short


short consensus repeat






bioluminescence resonance energy transfer


bimolecular fluorescence complementation


gastric inhibitory polypeptide receptor


glucagon-like peptide-1 receptor



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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