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

Journal of Molecular Endocrinology - Tập 53 Số 3 - Trang 319-330 - 2014
Hui Huang1, Ya‐Xiong Tao2
1Department of AnatomyPhysiology and Pharmacology, College of Veterinary Medicine, Auburn University, 212 Greene Hall, Auburn, Alabama 36849, USA.
2Department of AnatomyPhysiology and Pharmacology, College of Veterinary Medicine, Auburn University, 212 Greene Hall, Auburn, Alabama 36849, USA [email protected].

Tóm tắt

The melanocortin 3 receptor (MC3R) regulates several physiological functions, including feed efficiency, nutrient partitioning, fasting response, natriuresis, and immune reactions. Naturally occurring mutations in theMC3Rgene 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 Gs–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.

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Tài liệu tham khảo

1995, METHODS IN NEUROSCIENCE, 25, 366, 10.1016/S1043-9471(05)80049-7

Begriche, 2012, Genes, brain, and behavior, 11, 291, 10.1111/j.1601-183X.2012.00766.x

Breit, 2011, Molecular and cellular endocrinology, 331, 232, 10.1016/j.mce.2010.07.007

2009, Journal of Biological Chemistry, 284, 26411, 10.1074/jbc.M109.039339

Butler, 2000, Endocrinology, 141, 3518, 10.1210/en.141.9.3518

Chai, 2007, Regulatory peptides, 139, 115, 10.1016/j.regpep.2006.11.003

Chen, 2000, Nature genetics, 26, 97, 10.1038/79254

Chien, 2010, Science, 330, 1091, 10.1126/science.1197410

Chu, 1989, Developmental biology, 136, 104, 10.1016/0012-1606(89)90134-6

2008, American Journal of Respiratory and Critical Care Medicine, 178, 203, 10.1164/rccm.200710-1554OC

Cowley, 2001, Nature, 411, 480, 10.1038/35078085

Daniels, 2003, Brain research, 986, 1, 10.1016/S0006-8993(03)03162-7

2001, Journal of Biological Chemistry, 276, 29382, 10.1074/jbc.M103203200

2005, Molecular Pharmacology, 68, 1, 10.1124/mol.67.1.

Gantz, 1993, Journal of Biological Chemistry, 268, 8246, 10.1016/S0021-9258(18)53088-X

Getting, 2001, Journal of Leukocyte Biology, 69, 98, 10.1189/jlb.69.1.98

Getting, 2006, The FASEB Journal, 20, 2234, 10.1096/fj.06-6339com

Han, 2001, Structure (London), 9, 869, 10.1016/S0969-2126(01)00644-X

2012, Journal of Molecular Endocrinology, 49, 237, 10.1530/JME-12-0161

2014, INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES, 10, 817, 10.7150/ijbs.9625

2008, Science, 322, 1211, 10.1126/science.1164772

2013, Angewandte Chemie, 52, 6366, 10.1002/anie.201301924

2005, Journal of Biological Chemistry, 280, 29796, 10.1074/jbc.M413520200

2006, Journal of Biological Chemistry, 281, 2932, 10.1074/jbc.M508074200

2009, PNAS, 106, 14502, 10.1073/pnas.0903894106

2013, BIOCHIMICA ET BIOPHYSIC ACTA, 1832, 1939, 10.1016/j.bbadis.2013.06.006

2012, Journal of Molecular Endocrinology, 49, 221, 10.1530/JME-12-0162

Ni, 2003, Journal of Clinical Investigation, 111, 1251, 10.1172/JCI200316993

Okada, 2001, Trends in biochemical sciences, 26, 318, 10.1016/S0968-0004(01)01799-6

Palczewski, 2000, Science, 289, 739, 10.1126/science.289.5480.739

Patten, 2007, Regulatory peptides, 142, 111, 10.1016/j.regpep.2007.02.005

Rajagopal, 2010, Nature reviews. Drug discovery, 9, 373, 10.1038/nrd3024

Rasmussen, 2011, Nature, 469, 175, 10.1038/nature09648

Reiter, 2012, Annual review of pharmacology and toxicology, 52, 179, 10.1146/annurev.pharmtox.010909.105800

2012, PNAS, 109, E1489, 10.1073/pnas.1201994109

Roselli-Rehfuss, 1993, PNAS, 90, 8856, 10.1073/pnas.90.19.8856

2007, Science, 318, 1266, 10.1126/science.1150609

Rosenbaum, 2009, Nature, 459, 356, 10.1038/nature08144

Roskoski, 2012, Pharmacological research : the official journal of the Italian Pharmacological Society, 66, 105, 10.1016/j.phrs.2012.04.005

Sanchez-Laorden, 2009, Journal of cellular physiology, 220, 640, 10.1002/jcp.21804

Scheerer, 2008, Nature, 455, 497, 10.1038/nature07330

Sutton, 2008, Journal of Neuroscience, 28, 12946, 10.1523/JNEUROSCI.3615-08.2008

2010, The FASEB Journal, 24, 862, 10.1096/fj.09-142000

2007, BIOCHIMICA ET BIOPHYSIC ACTA, 1772, 1167, 10.1016/j.bbadis.2007.09.002

2008, PHARMACOLOGY THERAPEUTICS, 120, 129, 10.1016/j.pharmthera.2008.07.005

2010, CURRENT OPINION IN INVESTIGATIONAL DRUGS, 11, 1092

2014, Advances in pharmacology, 70, 135, 10.1016/B978-0-12-417197-8.00005-5

2014, FRONTIERS IN ENDOCRINOLOGY, 5, 131

2003, Endocrinology, 144, 4544, 10.1210/en.2003-0524

Tao, 2004, Journal of Clinical Endocrinology & Metabolism, 89, 3936, 10.1210/jc.2004-0367

2002, Molecular Endocrinology, 16, 1881, 10.1210/me.2001-0199

Tao, 2010, Methods in enzymology, 484, 267, 10.1016/B978-0-12-381298-8.00014-9

Marullo, 2007, Trends in Pharmacological Sciences (Regular ed.), 28, 416, 10.1016/j.tips.2007.06.006

2008, Journal of Biological Chemistry, 283, 31068, 10.1074/jbc.M805251200

2013, Science, 340, 615, 10.1126/science.1232808

2011, BIOCHIMICA ET BIOPHYSIC ACTA, 1812, 1190, 10.1016/j.bbadis.2011.06.008

Wang, 2008, Biochemical pharmacology, 76, 520, 10.1016/j.bcp.2008.05.026

Warne, 2012, Structure (London), 20, 841, 10.1016/j.str.2012.03.014

Wright, 2011, Nature genetics, 43, 539, 10.1038/ng.838

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Thông tin xuất bản

Journal of Molecular Endocrinology

Tập 53 Số 3

319-330

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