Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation

Ya-Xiong Tao; Deborah L Segaloff

doi:10.1210/jc.2004-0367

Back

Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation

Journal article

Open access

Peer reviewed

Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation

Ya-Xiong Tao and Deborah L Segaloff

The journal of clinical endocrinology and metabolism, Vol.89(8), pp.3936-3942

08/2004

DOI: 10.1210/jc.2004-0367

PMID: 15292330

Files and links (1)

url

https://doi.org/10.1210/jc.2004-0367View

Published (Version of record) Open Access

Abstract

Although melanocortin-4 receptor mutations are the cause of the most common monogenic form of obesity, the involvement of the melanocortin-3 receptor (MC3R) in the pathogenesis of obesity is unknown. Earlier studies failed to identify any mutations in obese patients except for the identification of two variants (K6T and I81V) that likely represent polymorphisms. However, a potential mutation (I183N) was recently reported from patients having high-fat contents. We report here the functional characterization of these variants. We show that K6T and I81V have ligand binding and signaling properties similar to wild-type (wt) MC3R, indicating that they are indeed polymorphisms. However, the other variant, I183N, completely lacks signaling in response to agonist stimulation, although it binds ligand with normal affinity and with only slightly decreased capacity. Coexpression of the wt and I183N MC3Rs showed that I183N does not exert dominant-negative activity on wt MC3R. These results provide supporting evidence for the hypothesis proposed in the original case report that MC3R mutation might be a genetic factor that confers susceptibility to obesity, likely due to haploinsufficiency. Further mutations at I183 revealed a discrete requirement for I183 in agonist-induced MC3R activation. The corresponding residue is also important for agonist-induced human melanocortin-4 receptor and lutropin receptor activation. In summary, we identify a residue that is critical for activation of G protein-coupled receptors.

Cell Line

Receptors, G-Protein-Coupled - metabolism

Threonine

Receptor, Melanocortin, Type 3 - genetics

Humans

Gene Expression Regulation

Receptors, LH - metabolism

Receptor, Melanocortin, Type 3 - metabolism

Genetic Variation

Codon

Receptors, LH - genetics

Lysine

Valine

Asparagine

Receptors, G-Protein-Coupled - genetics

Mutation

Receptors, LH - agonists

Receptor, Melanocortin, Type 3 - agonists

Isoleucine

Details

Title: Subtitle: Functional characterization of melanocortin-3 receptor variants identify a loss-of-function mutation involving an amino acid critical for G protein-coupled receptor activation
Creators: Ya-Xiong Tao - Department of Physiology and Biophysics, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. ya-xiong-tao@uiowa.edu
Deborah L Segaloff
Resource Type: Journal article
Publication Details: The journal of clinical endocrinology and metabolism, Vol.89(8), pp.3936-3942
DOI: 10.1210/jc.2004-0367
PMID: 15292330
ISSN: 0021-972X
eISSN: 1945-7197
Grant note: HD22196 / NICHD NIH HHS
Language: English
Date published: 08/2004
Academic Unit: Molecular Physiology and Biophysics; Obstetrics and Gynecology
Record Identifier: 9984083811002771

Metrics

12 Record Views

73 Times Cited - Web of Science

See more details