Regulation of G protein-coupled receptor signaling: specific dominant-negative effects of melanocortin 2 receptor accessory protein 2

Julien A Sebag; Patricia M Hinkle

doi:10.1126/scisignal.2000593

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Regulation of G protein-coupled receptor signaling: specific dominant-negative effects of melanocortin 2 receptor accessory protein 2

Journal article

Open access

Peer reviewed

Regulation of G protein-coupled receptor signaling: specific dominant-negative effects of melanocortin 2 receptor accessory protein 2

Julien A Sebag and Patricia M Hinkle

Science signaling, Vol.3(116), pp.ra28-ra28

04/06/2010

DOI: 10.1126/scisignal.2000593

PMCID: PMC2992810

PMID: 20371771

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https://www.ncbi.nlm.nih.gov/pmc/articles/2992810View

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Abstract

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs), which constitute the largest family of membrane proteins, mediate responses to diverse physiological stimuli. The presence of melanocortin 2 receptors (MC2Rs) on the plasma membrane requires the presence of either MC2R accessory protein (MRAP) or MRAP2, which are homologous accessory proteins. Here, we show that, whereas MRAP was essential for activation of MC2R signaling, MRAP2 was an endogenous inhibitor that competed with MRAP for binding to MC2R and decreased the potency of adrenocorticotropic hormone (ACTH), the endogenous agonist for MC2Rs, in stimulating the production of adenosine 3',5'-monophosphate (cAMP). ACTH bound with high affinity to MC2Rs in the presence of MRAP, but not MRAP2. The ability of MRAP and MRAP2 to influence ligand-binding affinity was specific to MC2R, because these proteins had little effect on the binding of NDP-alpha-melanocyte-stimulating hormone to MC4R or on its stimulation of cAMP responses. These results demonstrate that the balance of stimulatory and inhibitory accessory proteins can control the sensitivity of a GPCR to its natural agonist.

Cricetinae

Cricetulus

Enzyme-Linked Immunosorbent Assay

Receptors, G-Protein-Coupled - metabolism

Humans

DNA Primers - genetics

Reverse Transcriptase Polymerase Chain Reaction

Receptor, Melanocortin, Type 2 - metabolism

Carrier Proteins - genetics

Animals

Carrier Proteins - metabolism

Analysis of Variance

Cyclic AMP - biosynthesis

Membrane Proteins - chemistry

Cloning, Molecular

Carrier Proteins - chemistry

Signal Transduction - physiology

Membrane Proteins - metabolism

Dimerization

Adrenocorticotropic Hormone - metabolism

CHO Cells

Details

Title: Subtitle: Regulation of G protein-coupled receptor signaling: specific dominant-negative effects of melanocortin 2 receptor accessory protein 2
Creators: Julien A Sebag - Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
Patricia M Hinkle
Resource Type: Journal article
Publication Details: Science signaling, Vol.3(116), pp.ra28-ra28
DOI: 10.1126/scisignal.2000593
PMID: 20371771
PMCID: PMC2992810
NLM abbreviation: Sci Signal
ISSN: 1945-0877
eISSN: 1937-9145
Publisher: United States
Grant note: R01 DK019974 / NIDDK NIH HHS R01 DK019974-33 / NIDDK NIH HHS
Language: English
Date published: 04/06/2010
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984025404102771

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