Receptor Activity-modifying Protein-directed G Protein Signaling Specificity for the Calcitonin Gene-related Peptide Family of Receptors

The calcitonin gene-related peptide (CGRP) family of G protein-coupled receptors (GPCRs) is formed through the association of the calcitonin receptor-like receptor (CLR) and one of three receptor activity-modifying proteins (RAMPs). Binding of one of the three peptide ligands, CGRP, adrenomedullin (...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2016-10, Vol.291 (42), p.21925-21944
Main Authors: Weston, Cathryn, Winfield, Ian, Harris, Matthew, Hodgson, Rose, Shah, Archna, Dowell, Simon J, Mobarec, Juan Carlos, Woodlock, David A, Reynolds, Christopher A, Poyner, David R, Watkins, Harriet A, Ladds, Graham
Format: Article
Language:English
Subjects:
Adrenomedullin - genetics
Adrenomedullin - metabolism
Cyclic AMP - genetics
Cyclic AMP - metabolism
GTP-Binding Protein alpha Subunits - genetics
GTP-Binding Protein alpha Subunits - metabolism
HEK293 Cells
Humans
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Receptors, Calcitonin Gene-Related Peptide - genetics
Receptors, Calcitonin Gene-Related Peptide - metabolism
Second Messenger Systems - physiology
Signal Transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The calcitonin gene-related peptide (CGRP) family of G protein-coupled receptors (GPCRs) is formed through the association of the calcitonin receptor-like receptor (CLR) and one of three receptor activity-modifying proteins (RAMPs). Binding of one of the three peptide ligands, CGRP, adrenomedullin (AM), and intermedin/adrenomedullin 2 (AM2), is well known to result in a Gα -mediated increase in cAMP. Here we used modified yeast strains that couple receptor activation to cell growth, via chimeric yeast/Gα subunits, and HEK-293 cells to characterize the effect of different RAMP and ligand combinations on this pathway. We not only demonstrate functional couplings to both Gα and Gα but also identify a Gα component to CLR signaling in both yeast and HEK-293 cells, which is absent in HEK-293S cells. We show that the CGRP family of receptors displays both ligand- and RAMP-dependent signaling bias among the Gα , Gα , and Gα pathways. The results are discussed in the context of RAMP interactions probed through molecular modeling and molecular dynamics simulations of the RAMP-GPCR-G protein complexes. This study further highlights the importance of RAMPs to CLR pharmacology and to bias in general, as well as identifying the importance of choosing an appropriate model system for the study of GPCR pharmacology.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.m116.751362