Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ligands and Plasmids
2.2. Cell Culture and Transfection
2.3. Flow Cytometry Assay
2.4. Radioligand Ligand Binding Assays
2.5. Ligand-Stimulated cAMP Assays
2.6. Statistical Analysis
3. Results
3.1. Nucleotide and Deduced Amino Acid Sequences of hMRAP2s
3.2. Regulation of hMC3R Pharmacology by hMRAP1s and hMRAP2s
3.3. Regulation of hMC4R Pharmacology by hMRAP1s and hMRAP2s
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Smith, A.I.; Funder, J.W. Proopiomelanocortin processing in the pituitary, central nervous system, and peripheral tissues. Endocr. Rev. 1988, 9, 159–179. [Google Scholar] [CrossRef] [PubMed]
- Dores, R.M.; Lecaude, S. Trends in the evolution of the proopiomelanocortin gene. Gen. Comp. Endocrinol. 2005, 142, 81–93. [Google Scholar] [CrossRef] [PubMed]
- Gantz, I.; Miwa, H.; Konda, Y.; Shimoto, Y.; Tashiro, T.; Watson, S.J.; DelValle, J.; Yamada, T. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 1993, 268, 15174–15179. [Google Scholar] [CrossRef]
- Gantz, I.; Konda, Y.; Tashiro, T.; Shimoto, Y.; Miwa, H.; Munzert, G.; Watson, S.J.; DelValle, J.; Yamada, T. Molecular cloning of a novel melanocortin receptor. J. Biol. Chem. 1993, 268, 8246–8250. [Google Scholar] [CrossRef]
- Roselli-Rehfuss, L.; Mountjoy, K.G.; Robbins, L.S.; Mortrud, M.T.; Low, M.J.; Tatro, J.B.; Entwistle, M.L.; Simerly, R.B.; Cone, R.D. Identification of a receptor for γ melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system. Proc. Natl. Acad. Sci. USA 1993, 90, 8856–8860. [Google Scholar] [CrossRef] [Green Version]
- Mountjoy, K.G.; Mortrud, M.T.; Low, M.J.; Simerly, R.B.; Cone, R.D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 1994, 8, 1298–1308. [Google Scholar]
- Cone, R.D. Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 2005, 8, 571–578. [Google Scholar] [CrossRef]
- Tao, Y.X. Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. Mol. Cell. Endocrinol. 2005, 239, 1–14. [Google Scholar] [CrossRef]
- Huszar, D.; Lynch, C.A.; Fairchild-Huntress, V.; Dunmore, J.H.; Fang, Q.; Berkemeier, L.R.; Gu, W.; Kesterson, R.A.; Boston, B.A.; Cone, R.D.; et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997, 88, 131–141. [Google Scholar] [CrossRef] [Green Version]
- Balthasar, N.; Dalgaard, L.T.; Lee, C.E.; Yu, J.; Funahashi, H.; Williams, T.; Ferreira, M.; Tang, V.; McGovern, R.A.; Kenny, C.D.; et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 2005, 123, 493–505. [Google Scholar] [CrossRef]
- Chen, A.S.; Marsh, D.J.; Trumbauer, M.E.; Frazier, E.G.; Guan, X.M.; Yu, H.; Rosenblum, C.I.; Vongs, A.; Feng, Y.; Cao, L.; et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat. Genet. 2000, 26, 97–102. [Google Scholar] [CrossRef]
- Butler, A.A.; Kesterson, R.A.; Khong, K.; Cullen, M.J.; Pelleymounter, M.A.; Dekoning, J.; Baetscher, M.; Cone, R.D. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 2000, 141, 3518–3521. [Google Scholar] [CrossRef]
- Zhang, Y.; Kilroy, G.E.; Henagan, T.M.; Prpic-Uhing, V.; Richards, W.G.; Bannon, A.W.; Mynatt, R.L.; Gettys, T.W. Targeted deletion of melanocortin receptor subtypes 3 and 4, but not CART, alters nutrient partitioning and compromises behavioral and metabolic responses to leptin. FASEB J. 2005, 19, 1482–1491. [Google Scholar] [CrossRef]
- Tao, Y.X. Mutations in melanocortin-4 receptor and human obesity. Prog. Mol. Biol. Transl. Sci. 2009, 88, 173–204. [Google Scholar]
- Tao, Y.X. Mutations in the melanocortin-3 receptor (MC3R) gene: Impact on human obesity or adiposity. Curr. Opin. Investig. Drugs 2010, 11, 1092–1096. [Google Scholar]
- Tao, Y.X. The melanocortin-4 receptor: Physiology, pharmacology, and pathophysiology. Endocr. Rev. 2010, 31, 506–543. [Google Scholar] [CrossRef] [Green Version]
- Yang, Z.; Tao, Y.X. Mutations in melanocortin-3 receptor gene and human obesity. Prog. Mol. Biol. Transl. Sci. 2016, 140, 97–129. [Google Scholar] [CrossRef]
- Liu, T.; Ji, R.L.; Tao, Y.X. Naturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus. Pharmacol. Ther. 2022, 108044. [Google Scholar] [CrossRef]
- Versteeg, D.H.; Van Bergen, P.; Adan, R.A.; De Wildt, D.J. Melanocortins and cardiovascular regulation. Eur. J. Pharmacol. 1998, 360, 1–14. [Google Scholar] [CrossRef]
- Mioni, C.; Giuliani, D.; Cainazzo, M.M.; Leone, S.; Bazzani, C.; Grieco, P.; Novellino, E.; Tomasi, A.; Bertolini, A.; Guarini, S. Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors. Eur. J. Pharmacol. 2003, 477, 227–234. [Google Scholar] [CrossRef]
- Getting, S.J.; Christian, H.C.; Lam, C.W.; Gavins, F.N.; Flower, R.J.; Schioth, H.B.; Perretti, M. Redundancy of a functional melanocortin 1 receptor in the anti-inflammatory actions of melanocortin peptides: Studies in the recessive yellow (e/e) mouse suggest an important role for melanocortin 3 receptor. J. Immunol. 2003, 170, 3323–3330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Catania, A.; Gatti, S.; Colombo, G.; Lipton, J.M. Targeting melanocortin receptors as a novel strategy to control inflammation. Pharmacol. Rev. 2004, 56, 1–29. [Google Scholar] [CrossRef] [PubMed]
- Getting, S.J.; Riffo-Vasquez, Y.; Pitchford, S.; Kaneva, M.; Grieco, P.; Page, C.P.; Perretti, M.; Spina, D. A role for MC3R in modulating lung inflammation. Pulm. Pharmacol. Ther. 2008, 21, 866–873. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Patel, H.B.; Montero-Melendez, T.; Greco, K.V.; Perretti, M. Melanocortin receptors as novel effectors of macrophage responses in inflammation. Front. Immunol. 2011, 2, 41. [Google Scholar] [CrossRef] [Green Version]
- Wang, W.; Guo, D.Y.; Lin, Y.J.; Tao, Y.X. Melanocortin regulation of inflammation. Front. Endocrinol. 2019, 10, 683. [Google Scholar] [CrossRef]
- Chandramohan, G.; Durham, N.; Sinha, S.; Norris, K.; Vaziri, N.D. Role of γ melanocyte-stimulating hormone-renal melanocortin 3 receptor system in blood pressure regulation in salt-resistant and salt-sensitive rats. Metabolism 2009, 58, 1424–1429. [Google Scholar] [CrossRef]
- Lam, B.Y.H.; Williamson, A.; Finer, S.; Day, F.R.; Tadross, J.A.; Goncalves Soares, A.; Wade, K.; Sweeney, P.; Bedenbaugh, M.N.; Porter, D.T.; et al. MC3R links nutritional state to childhood growth and the timing of puberty. Nature 2021, 599, 436–441. [Google Scholar] [CrossRef]
- Xu, A.; Choi, K.L.; Wang, Y.; Permana, P.A.; Xu, L.Y.; Bogardus, C.; Cooper, G.J. Identification of novel putative membrane proteins selectively expressed during adipose conversion of 3T3-L1 cells. Biochem. Biophys. Res. Commun. 2002, 293, 1161–1167. [Google Scholar] [CrossRef]
- Metherell, L.A.; Chapple, J.P.; Cooray, S.; David, A.; Becker, C.; Ruschendorf, F.; Naville, D.; Begeot, M.; Khoo, B.; Nurnberg, P.; et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat. Genet. 2005, 37, 166–170. [Google Scholar] [CrossRef]
- Roy, S.; Rached, M.; Gallo-Payet, N. Differential regulation of the human adrenocorticotropin receptor [melanocortin-2 receptor (MC2R)] by human MC2R accessory protein isoforms alpha and beta in isogenic human embryonic kidney 293 cells. Mol. Endocrinol. 2007, 21, 1656–1669. [Google Scholar] [CrossRef] [Green Version]
- Sebag, J.A.; Hinkle, P.M. Melanocortin-2 receptor accessory protein MRAP forms antiparallel homodimers. Proc. Natl. Acad. Sci. USA 2007, 104, 20244–20249. [Google Scholar] [CrossRef] [Green Version]
- Tao, Y.X. Molecular chaperones and G protein-coupled receptor maturation and pharmacology. Mol. Cell. Endocrinol. 2020, 511, 110862. [Google Scholar] [CrossRef]
- Novoselova, T.; King, P.; Guasti, L.; Metherell, L.A.; Clark, A.J.L.; Chan, L.F. ACTH signalling and adrenal development: Lessons from mouse models. Endocr. Connect. 2019, 8, R122–R130. [Google Scholar] [CrossRef] [Green Version]
- Berruien, N.N.A.; Smith, C.L. Emerging roles of melanocortin receptor accessory proteins (MRAP and MRAP2) in physiology and pathophysiology. Gene 2020, 757, 144949. [Google Scholar] [CrossRef]
- Chan, L.F.; Webb, T.R.; Chung, T.T.; Meimaridou, E.; Cooray, S.N.; Guasti, L.; Chapple, J.P.; Egertova, M.; Elphick, M.R.; Cheetham, M.E.; et al. MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc. Natl. Acad. Sci. USA 2009, 106, 6146–6151. [Google Scholar] [CrossRef] [Green Version]
- Hinkle, P.M.; Serasinghe, M.N.; Jakabowski, A.; Sebag, J.A.; Wilson, K.R.; Haskell-Luevano, C. Use of chimeric melanocortin-2 and -4 receptors to identify regions responsible for ligand specificity and dependence on melanocortin 2 receptor accessory protein. Eur. J. Pharmacol. 2011, 660, 94–102. [Google Scholar] [CrossRef] [Green Version]
- Kay, E.I.; Botha, R.; Montgomery, J.M.; Mountjoy, K.G. hMRAPa increases α-MSH-induced hMC1R and hMC3R functional coupling and hMC4R constitutive activity. J. Mol. Endocrinol. 2013, 50, 203–215. [Google Scholar] [CrossRef] [Green Version]
- Asai, M.; Ramachandrappa, S.; Joachim, M.; Shen, Y.; Zhang, R.; Nuthalapati, N.; Ramanathan, V.; Strochlic, D.E.; Ferket, P.; Linhart, K.; et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 2013, 341, 275–278. [Google Scholar] [CrossRef] [Green Version]
- Novoselova, T.V.; Larder, R.; Rimmington, D.; Lelliott, C.; Wynn, E.H.; Gorrigan, R.J.; Tate, P.H.; Guasti, L.; O’Rahilly, S.; Clark, A.J.L. Loss of Mrap2 is associated with Sim1 deficiency and increased circulating cholesterol. J. Endocrinol. 2016, 230, 13–26. [Google Scholar] [CrossRef]
- Geets, E.; Zegers, D.; Beckers, S.; Verrijken, A.; Massa, G.; Van Hoorenbeeck, K.; Verhulst, S.; Van Gaal, L.; Van Hul, W. Copy number variation (CNV) analysis and mutation analysis of the 6q14.1-6q16.3 genes SIM1 and MRAP2 in Prader Willi like patients. Mol. Genet. Metab. 2016, 117, 383–388. [Google Scholar] [CrossRef]
- Baron, M.; Maillet, J.; Huyvaert, M.; Dechaume, A.; Boutry, R.; Loiselle, H.; Durand, E.; Toussaint, B.; Vaillant, E.; Philippe, J.; et al. Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension. Nat. Med. 2019, 25, 1733–1738. [Google Scholar] [CrossRef]
- Da Fonseca, A.C.P.; Abreu, G.M.; Zembrzuski, V.M.; Campos Junior, M.; Carneiro, J.R.I.; Nogueira Neto, J.F.; Magno, F.; Rosado, E.L.; Bozza, P.T.; de Cabello, G.M.K.; et al. Study of LEP, MRAP2 and POMC genes as potential causes of severe obesity in Brazilian patients. Eat. Weight Disord. 2021, 26, 1399–1408. [Google Scholar] [CrossRef]
- Sebag, J.A.; Zhang, C.; Hinkle, P.M.; Bradshaw, A.M.; Cone, R.D. Developmental control of the melanocortin-4 receptor by MRAP2 proteins in zebrafish. Science 2013, 341, 278–281. [Google Scholar] [CrossRef] [Green Version]
- Zhang, J.; Li, X.; Zhou, Y.; Cui, L.; Li, J.; Wu, C.; Wan, Y.; Li, J.; Wang, Y. The interaction of MC3R and MC4R with MRAP2, ACTH, α-MSH and AgRP in chickens. J. Endocrinol. 2017, 234, 155–174. [Google Scholar] [CrossRef]
- Yang, L.K.; Zhang, Z.R.; Wen, H.S.; Tao, Y.X. Characterization of channel catfish (Ictalurus punctatus) melanocortin-3 receptor reveals a potential network in regulation of energy homeostasis. Gen. Comp. Endocrinol. 2019, 277, 90–103. [Google Scholar] [CrossRef]
- Zhang, J.; Li, J.; Wu, C.; Hu, Z.; An, L.; Wan, Y.; Fang, C.; Zhang, X.; Li, J.; Wang, Y. The Asp298Asn polymorphism of melanocortin-4 receptor (MC4R) in pigs: Evidence for its potential effects on MC4R constitutive activity and cell surface expression. Anim. Genet. 2020, 51, 694–706. [Google Scholar] [CrossRef]
- Tao, M.; Ji, R.L.; Huang, L.; Fan, S.Y.; Liu, T.; Liu, S.J.; Tao, Y.X. Regulation of melanocortin-4 receptor pharmacology by two isoforms of melanocortin receptor accessory protein 2 in topmouth culter (Culter alburnus). Front. Endocrinol. 2020, 11, 538. [Google Scholar] [CrossRef]
- Ji, R.L.; Huang, L.; Wang, Y.; Liu, T.; Fan, S.Y.; Tao, M.; Tao, Y.X. Topmouth culter melanocortin-3 receptor: Regulation by two isoforms of melanocortin-2 receptor accessory protein 2. Endocr. Connect. 2021, 10, 1489–1501. [Google Scholar] [CrossRef] [PubMed]
- Wen, Z.Y.; Liu, T.; Qin, C.J.; Zou, Y.C.; Wang, J.; Li, R.; Tao, Y.X. MRAP2 interaction with melanocortin-4 receptor in snakehead (Channa argus). Biomolecules 2021, 11, 481. [Google Scholar] [CrossRef] [PubMed]
- Liang, J.; Li, L.; Jin, X.; Xu, B.; Pi, L.; Liu, S.; Zhu, W.; Zhang, C.; Luan, B.; Gong, L.; et al. Pharmacological effect of human melanocortin-2 receptor accessory protein 2 variants on hypothalamic melanocortin receptors. Endocrine 2018, 61, 94–104. [Google Scholar] [CrossRef] [PubMed]
- Soletto, L.; Hernandez-Balfago, S.; Rocha, A.; Scheerer, P.; Kleinau, G.; Cerdá-Reverter, J.M. Melanocortin receptor accessory protein 2-induced adrenocorticotropic hormone response of human melanocortin 4 receptor. J. Endocr. Soc. 2019, 3, 314–323. [Google Scholar] [CrossRef] [Green Version]
- Steiner, A.L.; Kipnis, D.M.; Utiger, R.; Parker, C. Radioimmunoassay for the measurement of adenosine 3’,5’-cyclic phosphate. Proc. Natl. Acad. Sci. USA 1969, 64, 367–373. [Google Scholar] [CrossRef] [Green Version]
- Mo, X.L.; Yang, R.; Tao, Y.X. Functions of transmembrane domain 3 of human melanocortin-4 receptor. J. Mol. Endocrinol. 2012, 49, 221–235. [Google Scholar] [CrossRef] [Green Version]
- Tao, Y.X.; Segaloff, D.L. Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. Endocrinology 2003, 144, 4544–4551. [Google Scholar] [CrossRef]
- Chen, C.; Okayama, H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol. Cell. Biol. 1987, 7, 2745–2752. [Google Scholar]
- Wang, S.X.; Fan, Z.C.; Tao, Y.X. Functions of acidic transmembrane residues in human melanocortin-3 receptor binding and activation. Biochem. Pharmacol. 2008, 76, 520–530. [Google Scholar] [CrossRef] [Green Version]
- Zhang, K.Q.; Hou, Z.S.; Wen, H.S.; Li, Y.; Qi, X.; Li, W.J.; Tao, Y.X. Melanocortin-4 receptor in spotted sea bass, Lateolabrax maculatus: Cloning, tissue distribution, physiology, and pharmacology. Front. Endocrinol. 2019, 10, 705. [Google Scholar] [CrossRef] [Green Version]
- Tao, Y.X.; Huang, H.; Wang, Z.Q.; Yang, F.; Williams, J.N.; Nikiforovich, G.V. Constitutive activity of neural melanocortin receptors. Methods Enzymol. 2010, 484, 267–279. [Google Scholar]
- Black, D.L. Mechanisms of alternative pre-messenger RNA splicing. Annu. Rev. Biochem. 2003, 72, 291–336. [Google Scholar] [CrossRef] [Green Version]
- Pan, Q.; Shai, O.; Lee, L.J.; Frey, B.J.; Blencowe, B.J. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 2008, 40, 1413–1415. [Google Scholar] [CrossRef]
- Wahl, M.C.; Will, C.L.; Luhrmann, R. The spliceosome: Design principles of a dynamic RNP machine. Cell 2009, 136, 701–718. [Google Scholar] [CrossRef] [Green Version]
- Liang, Q.; Wu, N.; Zaneveld, S.; Liu, H.; Fu, S.; Wang, K.; Bertrand, R.; Wang, J.; Li, Y.; Chen, R. Transcript isoforms of Reep6 have distinct functions in the retina. Hum. Mol. Genet. 2021, 30, 1907–1918. [Google Scholar] [CrossRef]
- Sebag, J.A.; Hinkle, P.M. Regions of melanocortin 2 (MC2) receptor accessory protein necessary for dual topology and MC2 receptor trafficking and signaling. J. Biol. Chem. 2009, 284, 610–618. [Google Scholar] [CrossRef] [Green Version]
- Hinkle, P.M.; Sebag, J.A. Structure and function of the melanocortin 2 receptor accessory protein (MRAP). Mol. Cell. Endocrinol. 2009, 300, 25–31. [Google Scholar] [CrossRef] [Green Version]
- Dores, R.M. Hypothesis and theory: Revisiting views on the co-evolution of the melanocortin receptors and the accessory proteins, MRAP1 and MRAP2. Front. Endocrinol. 2016, 7, 79. [Google Scholar] [CrossRef] [Green Version]
- Dores, R.M.; Chapa, E. Hypothesis and Theory: Evaluating the co-evolution of the melanocortin-2 receptor and the accessory protein MRAP1. Front. Endocrinol. 2021, 12, 747843. [Google Scholar] [CrossRef]
- Malik, S.; Dolan, T.M.; Maben, Z.J.; Hinkle, P.M. Adrenocorticotropic hormone (ACTH) responses require actions of the melanocortin-2 receptor accessory protein on the extracellular surface of the plasma membrane. J. Biol. Chem. 2015, 290, 27972–27985. [Google Scholar] [CrossRef] [Green Version]
- Agulleiro, M.J.; Roy, S.; Sanchez, E.; Puchol, S.; Gallo-Payet, N.; Cerdá-Reverter, J.M. Role of melanocortin receptor accessory proteins in the function of zebrafish melanocortin receptor type 2. Mol. Cell. Endocrinol. 2010, 320, 145–152. [Google Scholar] [CrossRef] [Green Version]
- Liang, L.; Sebag, J.A.; Eagelston, L.; Serasinghe, M.N.; Veo, K.; Reinick, C.; Angleson, J.; Hinkle, P.M.; Dores, R.M. Functional expression of frog and rainbow trout melanocortin 2 receptors using heterologous MRAP1s. Gen. Comp. Endocrinol. 2011, 174, 5–14. [Google Scholar] [CrossRef]
- Tai, X.; Xue, S.; Zhang, C.; Liu, Y.; Chen, J.; Han, Y.; Lin, G.; Zhang, C. Pharmacological evaluation of MRAP proteins on Xenopus neural melanocortin signaling. J. Cell. Physiol. 2021, 236, 6344–6361. [Google Scholar] [CrossRef]
- Kay, E.I.; Botha, R.; Montgomery, J.M.; Mountjoy, K.G. hMRAPα, but not hMRAP2, enhances hMC4R constitutive activity in HEK293 cells and this is not dependent on hMRAPα induced changes in hMC4R complex N-linked glycosylation. PLoS ONE 2015, 10, e0140320. [Google Scholar] [CrossRef] [PubMed]
- Josep Agulleiro, M.; Cortes, R.; Fernandez-Duran, B.; Navarro, S.; Guillot, R.; Meimaridou, E.; Clark, A.J.; Cerdá-Reverter, J.M. Melanocortin 4 receptor becomes an ACTH receptor by coexpression of melanocortin receptor accessory protein 2. Mol. Endocrinol. 2013, 27, 1934–1945. [Google Scholar] [CrossRef] [PubMed]
- Rao, Y.Z.; Chen, R.; Zhang, Y.; Tao, Y.X. Orange-spotted grouper melanocortin-4 receptor: Modulation of signaling by MRAP2. Gen. Comp. Endocrinol. 2019, 284, 113234. [Google Scholar] [CrossRef] [PubMed]
- Wang, M.; Chen, Y.J.; Zhu, M.; Xu, B.X.; Guo, W.X.; Lyu, Y.S.; Zhang, C. Pharmacological modulation of melanocortin-4 receptor by melanocortin receptor accessory protein 2 in Nile tilapia. Gen. Comp. Endocrinol. 2019, 282, 113219. [Google Scholar] [CrossRef]
- Srinivasan, S.; Lubrano-Berthelier, C.; Govaerts, C.; Picard, F.; Santiago, P.; Conklin, B.R.; Vaisse, C. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans. J. Clin. Investig. 2004, 114, 1158–1164. [Google Scholar] [CrossRef] [Green Version]
- Tao, Y.X. Constitutive activation of G protein-coupled receptors and diseases: Insights into mechanism of activation and therapeutics. Pharmacol. Ther. 2008, 120, 129–148. [Google Scholar] [CrossRef] [Green Version]
- Tao, Y.X. Constitutive activity in melanocortin-4 receptor: Biased signaling of inverse agonists. Adv. Pharmacol. 2014, 70, 135–154. [Google Scholar] [CrossRef]
- Gillyard, T.; Fowler, K.; Williams, S.Y.; Cone, R.D. Obesity-associated mutant melanocortin-4 receptors with normal Gαs coupling frequently exhibit other discoverable pharmacological and biochemical defects. J. Neuroendocrinol. 2019, 31, e12795. [Google Scholar] [CrossRef]
- Rouault, A.A.J.; Rosselli-Murai, L.K.; Hernandez, C.C.; Gimenez, L.E.; Tall, G.G.; Sebag, J.A. The GPCR accessory protein MRAP2 regulates both biased signaling and constitutive activity of the ghrelin receptor GHSR1a. Sci. Signal. 2020, 13. [Google Scholar] [CrossRef] [Green Version]
- Chaly, A.L.; Srisai, D.; Gardner, E.E.; Sebag, J.A. The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1. eLife 2016, 5, e12397. [Google Scholar] [CrossRef] [Green Version]
- Webb, T.R.; Chan, L.; Cooray, S.N.; Cheetham, M.E.; Chapple, J.P.; Clark, A.J. Distinct melanocortin 2 receptor accessory protein domains are required for melanocortin 2 receptor interaction and promotion of receptor trafficking. Endocrinology 2009, 150, 720–726. [Google Scholar] [CrossRef] [Green Version]
- Rouault, A.A.J.; Lee, A.A.; Sebag, J.A. Regions of MRAP2 required for the inhibition of orexin and prokineticin receptor signaling. Biochim. Biophys. Acta Mol. Cell. Res. 2017, 1864, 2322–2329. [Google Scholar] [CrossRef]
Bmax (%) | α-MSH Binding | ACTH Binding | |
---|---|---|---|
IC50 (nM) | IC50 (nM) | ||
hMC3R | 100 | 667.50 ± 152.87 | 85.81 ± 14.16 |
hMC3R+MRAP1a | 85.69 ± 7.43 | 360.20 ± 47.09 | 17.49 ± 3.42 a |
hMC3R+MRAP1b | 63.26 ± 6.19 a | 490.84 ± 179.41 | 42.75 ± 13.05 |
hMC3R+MRAP2a | 91.42 ± 8.31 | 820.24 ± 177.02 | 80.64 ± 13.63 |
hMC3R+MRAP2b | 102.49 ± 7.93 | 895.85 ± 131.95 | 65.03 ± 10.47 |
hMC3R+MRAP2c | 87.77 ± 6.35 | 479.51 ± 71.39 | 80.94 ± 14.78 |
α-MSH | ACTH(1–24) | ||||
---|---|---|---|---|---|
Basal (%) | EC50 (nM) | Rmax (%) | EC50 (nM) | Rmax (%) | |
hMC3R | 100 | 1.39 ± 0.16 | 100 | 4.63 ± 0.81 | 100 |
hMC3R+MRAP1a | 77.06 ± 5.95 b | 1.31 ± 0.28 | 58.22 ± 9.55 a | 1.81 ± 0.65 | 58.54 ± 8.98 b |
hMC3R+MRAP1b | 58.25 ± 5.35 c | 5.46 ± 1.99 | 52.41 ± 11.58 a | 8.39 ± 2.58 | 34.26 ± 3.95 c |
hMC3R+MRAP2a | 74.18 ± 10.50 a | 3.82 ± 1.14 | 39.07 ± 8.66 b | 4.91 ± 2.15 | 46.85 ± 17.28 a |
hMC3R+MRAP2b | 67.39 ± 7.43 b | 1.25 ± 0.36 | 86.61 ± 10.49 | 2.07 ± 0.85 | 66.85 ± 16.92 a |
hMC3R+MRAP2c | 64.36 ± 11.57 a | 1.79 ± 0.32 | 59.07 ± 6.60 b | 3.39 ± 1.19 | 52.10 ± 16.25 a |
α-MSH | ACTH(1–24) | ||
---|---|---|---|
Bmax (%) | IC50 (nM) | IC50 (nM) | |
hMC4R | 100 | 335.51 ± 32.19 | 53.62 ± 13.46 |
hMC4R+MRAP1a | 48.96 ± 7.57 a | 234.73 ± 79.01 | 26.16 ± 13.77 |
hMC4R+MRAP1b | 48.01 ± 8.94 a | 289.67 ± 77.10 | 19.08 ± 2.52 a |
hMC4R+MRAP2a | 143.32 ± 11.76 a | 355.93 ± 39.71 | 123.18 ± 22.12 a |
hMC4R+MRAP2b | 133.72 ± 14.64 | 330.42 ± 70.97 | 55.78 ± 18.24 |
hMC4R+MRAP2c | 132.51 ± 9.31 | 380.19 ± 87.45 | 69.64 ± 10.53 |
α-MSH | ACTH(1–24) | ||||
---|---|---|---|---|---|
Basal (%) | EC50 (nM) | Rmax (%) | EC50 (nM) | Rmax (%) | |
hMC4R | 100 | 5.10 ± 0.80 | 100 | 1.81 ± 0.34 | |
hMC4R+MRAP1a | 659.91 ± 97.58 c | 4.79 ± 2.31 | 47.81 ± 6.97 a | 0.33 ± 0.05 a | 93.28 ± 23.57 |
hMC4R+MRAP1b | 152.41 ± 12.81 b | 4.27 ± 1.33 | 49.20 ± 7.90 a | 0.89 ± 0.19 | 66.29 ± 12.29 a |
hMC4R+MRAP2a | 55.88 ± 8.92 b | 3.10 ± 0.14 | 56.90 ± 18.75 a | 3.20 ± 0.41 | 102.73 ± 22.28 |
hMC4R+MRAP2b | 66.34 ± 7.52 b | 3.26 ± 0.63 | 45.96 ± 13.34 b | 1.89 ± 0.28 | 121.35 ± 22.98 |
hMC4R+MRAP2c | 65.37 ± 7.55 b | 3.43 ± 0.96 | 33.04 ± 7.10 b | 3.27 ± 0.86 | 81.54 ± 14.07 |
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Ji, R.-L.; Tao, Y.-X. Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2. Biomolecules 2022, 12, 244. https://doi.org/10.3390/biom12020244
Ji R-L, Tao Y-X. Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2. Biomolecules. 2022; 12(2):244. https://doi.org/10.3390/biom12020244
Chicago/Turabian StyleJi, Ren-Lei, and Ya-Xiong Tao. 2022. "Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2" Biomolecules 12, no. 2: 244. https://doi.org/10.3390/biom12020244