Constitutive Activation of Tethered-Peptide/Corticotropin-Releasing Factor Receptor Chimeras

Constitutive activity, or ligand-independent activity, of mutant G protein-coupled receptors (GPCRs) has been described extensively and implicated in the pathology of many diseases. Using the corticotropin-releasing factor (CRF) receptor and the thrombin receptor as a model, we present a ligand-depe...

Full description

Saved in:

Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 18; pp. 10277 - 10281
Main Authors:	Nielsen, S M, Nielsen, L Z, Hjorth, S A, Perrin, M H, Vale, W W
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences of the United States of America 29-08-2000 National Acad Sciences National Academy of Sciences The National Academy of Sciences
Subjects:	Agonists Amino Acid Sequence Amino acids Animals Biological Sciences Chimeras Corticotropin-Releasing Hormone - antagonists & inhibitors Corticotropin-Releasing Hormone - pharmacology COS Cells Epitopes Hormones Humans Hypothalamic regulation Ligands Models, Molecular Molecular Sequence Data Mutation Pathology Peptide Fragments - chemistry Peptide Fragments - metabolism Peptide Fragments - pharmacology Peptides Pharmacology Point mutation Protein Structure, Secondary Proteins Receptors Receptors, Corticotropin-Releasing Hormone - chemistry Receptors, Corticotropin-Releasing Hormone - genetics Receptors, Corticotropin-Releasing Hormone - physiology Receptors, Thrombin - chemistry Receptors, Thrombin - genetics Receptors, Thrombin - physiology Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - metabolism Thrombin receptors Transfection Urocortins Vehicles
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	Constitutive activity, or ligand-independent activity, of mutant G protein-coupled receptors (GPCRs) has been described extensively and implicated in the pathology of many diseases. Using the corticotropin-releasing factor (CRF) receptor and the thrombin receptor as a model, we present a ligand-dependent constitutive activation of a GPCR. A chimera in which the N-terminal domain of the CRF receptor is replaced by the amino-terminal 16 residues of CRF displays significant levels of constitutive activation. The activity, as measured by intracellular levels of cAMP, is blocked in a dose-dependent manner by the nonpeptide antagonist antalarmin. These results support a propinquity effect in CRF receptor activation, in which the amino-terminal portion of the CRF peptide is presented to the body of the receptor in the proper proximity for activation. This form of ligand-dependent constitutive activation may be of general applicability for the creation of constitutively activated GPCRs that are regulated by peptide ligands such as CRF. These chimeras may prove useful in analyzing mechanisms of receptor regulation and in the structural analysis of ligand-activated receptors.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Novo Nordisk A/S, DK-2880 Bagsværd, Copenhagen, Denmark. Contributed by Wylie W. Vale To whom reprint requests should be addressed. E-mail: vale@salk.edu.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.97.18.10277