Alternative G protein coupling and biased agonism: New insights into melanocortin-4 receptor signalling

Breit, Andreas; Büch, Thomas; Boekhoff, Ingrid; Solinski, Hans Jürgen; Damm, Ellen; Gudermann, Thomas

doi:10.1016/j.mce.2010.07.007

Cited by 59 publications

(50 citation statements)

References 103 publications

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“…To the best of our knowledge, this is the first report describing biased signaling in MC3R. Biased signaling induced either by mutation or by biased ligand has been reported in the MC4R (Patten et al 2007, Büch et al 2009, Huang & Tao 2012, Mo et al 2012, Mo & Tao 2013; reviewed by Breit et al (2011) andTao (2014)) and several other GPCRs (reviewed by Violin & Lefkowitz (2007) and Lefkowitz (2013)). It has been suggested that biased ligands interact with different residues of the receptor and, therefore, induce different conformational changes in b 1 -AR (Warne et al 2012) and serotonin receptors (Wacker et al 2013).…”

Section: Discussionmentioning

confidence: 79%

“…In addition to biased ligands, biased signaling may also be induced by mutations in the GPCRs (Rajagopal et al 2010). We and others have previously identified both biased ligands and receptors in MC4R (Patten et al 2007, Büch et al 2009, Huang & Tao 2012, Mo et al 2012, Mo & Tao 2013; reviewed by Breit et al (2011) and Tao (2014)). However, until now, no biased signaling of MC3R has been reported.…”

Section: Introductionmentioning

confidence: 99%

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Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Huang¹,

Tao²

2014

Journal of Molecular Endocrinology

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The melanocortin 3 receptor (MC3R) regulates several physiological functions, including feed efficiency, nutrient partitioning, fasting response, natriuresis, and immune reactions. Naturally occurring mutations in the MC3R gene have been shown to be associated with increased adiposity and lung diseases such as tuberculosis and cystic fibrosis. The DRY motif at the cytoplasmic end of transmembrane domain 3 (TM3) and the second intracellular loop 2 (ICL2) are known to be important for receptor function in several G protein-coupled receptors (GPCRs). To gain a better understanding of the functions of this domain in MC3R, we performed alanine-scanning mutagenesis on 18 residues. We showed that alanine mutation of 11 residues reduced the maximal binding and maximal cAMP production stimulated by agonists. Mutation of two residues did not change maximal binding but resulted in impaired signaling in the G s -cAMP pathway. Mutation of five residues impaired signaling in the ERK1/2 pathway. We have also shown that alanine mutants of seven residues that were defective in the cAMP pathway were not defective in the ERK1/2 pathway, demonstrating biased signaling. In summary, we demonstrated that the cytoplasmic end of TM3 and the ICL2 were critical for MC3R function. We also reported for the first time biased signaling in MC3R. Key Words" melanocortin 3 receptor " intracellular loop 2 " DRY motif " MAP kinase " biased signaling

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Huang¹,

Tao²

2014

Journal of Molecular Endocrinology

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“…The enhanced signaling of chim5-chim7 might also be due to signaling from MC4R homodimer to PTXsensitive G-proteins (Buch et al 2009); however, signaling from MC4R to other G-proteins than Gs depends on the cell system used (Breit et al 2011). In COS-7 cells, no reduction in basal activity was observed for the MC4R mutant Asp90Asn after NDP-a-MSH challenge (Biebermann et al 2003), as has been found in HEK293 cells (Buch et al 2009).…”

Section: Tmh3 and Icl2 Constrain The Inactive Statementioning

confidence: 84%

Inhibition of melanocortin-4 receptor dimerization by substitutions in intracellular loop 2

Piechowski¹,

Rediger²,

Lagemann³

et al. 2013

Journal of Molecular Endocrinology

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Obesity is one of the most challenging global health problems. One key player in energy homeostasis is the melanocortin-4 receptor (MC4R), which is a family A G-protein-coupled receptor (GPCR). It has recently been shown that MC4R has the capacity to form homo-or heterodimers. Dimerization of GPCRs is of great importance for signaling regulation, with major pharmacological implications. Unfortunately, not enough is yet known about the detailed structural properties of MC4R dimers or the functional consequences of receptor dimerization. Our goal, therefore, was to explore specific properties related to MC4R dimerization. First, we aimed to induce the dissociation of dimers to monomers and to compare the functional parameters of wild-type and MC4R variants. To inhibit homodimerization, we designed MC4R chimeras with the cannabinoid-1 receptor, a receptor that does not interact with MC4R. Indeed, we identified several substitutions in the intracellular loop 2 (ICL2) and adjacent regions of transmembrane helix 3 (TMH3) and TMH4 that lead to partial dimer dissociation. Interestingly, the capacity for signaling activity was generally increased in these MC4R variants, although receptor expression remained unchanged. This increase in activity for dissociated receptors might indicate a link between receptor dimerization and signaling capacity. Moreover, dimer dissociation was also observed in a naturally occurring activating MC4R mutation in ICL2. Taken together, this study provides new information on the structural prerequisites for MC4R dimerization and identifies an approach to induce the dissociation of MC4R dimers. This might be useful for further investigation of pharmacological properties.

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“…FTY720, 17 a pan-S1P receptor agonist 5,14 that binds to four of the S1P receptors except for S1P 2 , has been demonstrated to exert its beneficiary effect by sequestering lymphocytes in MS patients through agonism of the S1P 1 receptor. 18,19 In addition, several other S1P 1 selective agonists have been reported to have similar therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Predictability of Peripheral Lymphocyte Reduction of Novel S1P1 Agonists by In Vitro GPCR Signaling Profile

McElvain

Fiorino

et al. 2013

SLAS Discovery

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Surrogate readouts of G-protein-coupled receptor signaling pathways using highly engineered systems are often employed in the drug discovery process. However, accumulating data have demonstrated the importance of selecting relevant biological activity rather than technically facile assays to support high-throughout screening and subsequent structureactivity relationship studies. Here we report a case study using sphingosine-1-phosphate receptor 1 (S1P 1 ) as the model system to compare compound activity in six different in vitro assays with their ability to predict in vivo efficacy. S1P 1 has long been validated as a therapeutic target for autoimmune diseases. In this article, in vivo and in vitro studies on 19 S1P 1 agonists are reported. In vitro activities of these S1P 1 agonists, together with S1P and FTY720p, on Ca 2+ mobilization, adenylyl cyclase inhibition, extracellular signal-related kinase (ERK) phosphorylation, β-arrestin recruitment, and receptor internalization, were determined. The in vitro potency of these compounds was correlated with their ability to induce peripheral lymphocyte reduction. The results revealed that inhibition of adenylyl cyclase and induction of β-arrestin recruitment and receptor internalization are good indicators to predict in vivo efficacy, whereas induction of Ca 2+ mobilization through G qi/5coupling and ERK phosphorylation is irrelevant. This study demonstrated the importance of identifying an appropriate in vitro assay to predict in vivo activity based on the biological relevance in the drug discovery setting.

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Alternative G protein coupling and biased agonism: New insights into melanocortin-4 receptor signalling

Cited by 59 publications

References 103 publications

Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Functions of the DRY motif and intracellular loop 2 of human melanocortin 3 receptor

Inhibition of melanocortin-4 receptor dimerization by substitutions in intracellular loop 2

Predictability of Peripheral Lymphocyte Reduction of Novel S1P1 Agonists by In Vitro GPCR Signaling Profile

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