Apo-Ghrelin Receptor Forms Heteromers with DRD2 in Hypothalamic Neurons and Is Essential for Anorexigenic Effects of DRD2 Agonism

Albizu, 2010, Time-resolved FRET between GPCR ligands reveals oligomers in native tissues, Nat. Chem. Biol., 6, 587, 10.1038/nchembio.396 Bonacci, 2006, Differential targeting of Gbetagamma-subunit signaling with small molecules, Science, 312, 443, 10.1126/science.1120378 Bulenger, 2005, Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation, Trends Pharmacol. Sci., 26, 131, 10.1016/j.tips.2005.01.004 Button, 1993, Aequorin-expressing mammalian cell lines used to report Ca2+ mobilization, Cell Calcium, 14, 663, 10.1016/0143-4160(93)90091-J Canals, 2008, Constitutive activity of the cannabinoid CB1 receptor regulates the function of co-expressed Mu opioid receptors, J. Biol. Chem., 283, 11424, 10.1074/jbc.M710300200 Comings, 1996, Genetic variants of the human obesity (OB) gene: association with body mass index in young women, psychiatric symptoms, and interaction with the dopamine D2 receptor (DRD2) gene, Mol. Psychiatry, 1, 325 Costantini, 2011, GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs, Neuroendocrinology, 94, 158, 10.1159/000328968 Cowley, 2003, The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis, Neuron, 37, 649, 10.1016/S0896-6273(03)00063-1 Dixit, 2007, Ghrelin promotes thymopoiesis during aging, J. Clin. Invest., 117, 2778, 10.1172/JCI30248 Epstein, 2007, Food reinforcement, the dopamine D2 receptor genotype, and energy intake in obese and nonobese humans, Behav. Neurosci., 121, 877, 10.1037/0735-7044.121.5.877 Feighner, 1998, Structural requirements for the activation of the human growth hormone secretagogue receptor by peptide and nonpeptide secretagogues, Mol. Endocrinol., 12, 137, 10.1210/mend.12.1.0051 Feighner, 1999, Receptor for motilin identified in the human gastrointestinal system, Science, 284, 2184, 10.1126/science.284.5423.2184 Fetissov, 2002, Expression of dopaminergic receptors in the hypothalamus of lean and obese Zucker rats and food intake, Am. J. Physiol. Regul. Integr. Comp. Physiol., 283, R905, 10.1152/ajpregu.00092.2002 Fung, 2009, Ligand-regulated oligomerization of beta(2)-adrenoceptors in a model lipid bilayer, EMBO J., 28, 3315, 10.1038/emboj.2009.267 Grouselle, 2008, Pulsatile cerebrospinal fluid and plasma ghrelin in relation to growth hormone secretion and food intake in the sheep, J. Neuroendocrinol., 20, 1138, 10.1111/j.1365-2826.2008.01770.x Guan, 1997, Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues, Brain Res. Mol. Brain Res., 48, 23, 10.1016/S0169-328X(97)00071-5 Guo, 2005, Crosstalk in G protein-coupled receptors: changes at the transmembrane homodimer interface determine activation, Proc. Natl. Acad. Sci. USA, 102, 17495, 10.1073/pnas.0508950102 Han, 2009, Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation, Nat. Chem. Biol., 5, 688, 10.1038/nchembio.199 Holst, 2004, Common structural basis for constitutive activity of the ghrelin receptor family, J. Biol. Chem., 279, 53806, 10.1074/jbc.M407676200 Holst, 2007, Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism, J. Biol. Chem., 282, 15799, 10.1074/jbc.M609796200 Howard, 1996, A receptor in pituitary and hypothalamus that functions in growth hormone release, Science, 273, 974, 10.1126/science.273.5277.974 Inglese, 1994, Functionally active targeting domain of the beta-adrenergic receptor kinase: an inhibitor of G beta gamma-mediated stimulation of type II adenylyl cyclase, Proc. Natl. Acad. Sci. USA, 91, 3637, 10.1073/pnas.91.9.3637 Jiang, 2006, Ghrelin amplifies dopamine signaling by crosstalk involving formation of GHS-R/D1R heterodimers, Mol. Endocrinol., 20, 1772, 10.1210/me.2005-0084 Johnson, 2010, Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats, Nat. Neurosci., 13, 635, 10.1038/nn.2519 Jones, 1998, GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2, Nature, 396, 674, 10.1038/25348 Kern, 2007, The low-density lipoprotein class A module of the relaxin receptor (leucine-rich repeat containing G-protein coupled receptor 7): its role in signaling and trafficking to the cell membrane, Endocrinology, 148, 1181, 10.1210/en.2006-1086 Koch, 1994, Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G beta gamma-mediated signaling, J. Biol. Chem., 269, 6193, 10.1016/S0021-9258(17)37587-7 Kojima, 1999, Ghrelin is a growth-hormone-releasing acylated peptide from stomach, Nature, 402, 656, 10.1038/45230 Korner, 2003, Treatment with cabergoline is associated with weight loss in patients with hyperprolactinemia, Obes. Res., 11, 311, 10.1038/oby.2003.46 Kvernmo, 2006, A review of the receptor-binding and pharmacokinetic properties of dopamine agonists, Clin. Ther., 28, 1065, 10.1016/j.clinthera.2006.08.004 Mancia, 2008, Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor, EMBO Rep., 9, 363, 10.1038/embor.2008.27 Maurel, 2008, Cell-surface protein-protein interaction analysis with time-resolved FRET and snap-tag technologies: application to GPCR oligomerization, Nat. Methods, 5, 561, 10.1038/nmeth.1213 Meguid, 2000, Hypothalamic dopamine and serotonin in the regulation of food intake, Nutrition, 16, 843, 10.1016/S0899-9007(00)00449-4 Milligan, 2009, G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function, Br. J. Pharmacol., 158, 5, 10.1111/j.1476-5381.2009.00169.x Missale, 1998, Dopamine receptors: from structure to function, Physiol. Rev., 78, 189, 10.1152/physrev.1998.78.1.189 Moulin, 2007, Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo evaluations, J. Med. Chem., 50, 5790, 10.1021/jm0704550 Namkung, 2004, Protein kinase C mediates phosphorylation, desensitization, and trafficking of the D2 dopamine receptor, J. Biol. Chem., 279, 49533, 10.1074/jbc.M408319200 Palmiter, 2007, Is dopamine a physiologically relevant mediator of feeding behavior?, Trends Neurosci., 30, 375, 10.1016/j.tins.2007.06.004 Patchett, 1995, Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue, Proc. Natl. Acad. Sci. USA, 92, 7001, 10.1073/pnas.92.15.7001 Petersen, 2009, In vivo characterization of high Basal signaling from the ghrelin receptor, Endocrinology, 150, 4920, 10.1210/en.2008-1638 Pijl, 2003, Reduced dopaminergic tone in hypothalamic neural circuits: expression of a “thrifty” genotype underlying the metabolic syndrome?, Eur. J. Pharmacol., 480, 125, 10.1016/j.ejphar.2003.08.100 Rives, 2009, Crosstalk between GABAB and mGlu1a receptors reveals new insight into GPCR signal integration, EMBO J., 28, 2195, 10.1038/emboj.2009.177 Smith, 2010, Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes, Pharmacol. Rev., 62, 701, 10.1124/pr.110.002667 Smith, 1996, Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland, Recent Prog. Horm. Res., 51, 261 Smith, 1997, Peptidomimetic regulation of growth hormone secretion, Endocr. Rev., 18, 621, 10.1210/edrv.18.5.0316 Stice, 2008, Relation between obesity and blunted striatal response to food is moderated by TaqIA A1 allele, Science, 322, 449, 10.1126/science.1161550 Sun, 2004, Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor, Proc. Natl. Acad. Sci. USA, 101, 4679, 10.1073/pnas.0305930101 Sun, 2006, Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice, Cell Metab., 3, 379, 10.1016/j.cmet.2006.04.004 Terrillon, 2004, Roles of G-protein-coupled receptor dimerization, EMBO Rep., 5, 30, 10.1038/sj.embor.7400052 Vilardaga, 2008, Conformational cross-talk between alpha2A-adrenergic and mu-opioid receptors controls cell signaling, Nat. Chem. Biol., 4, 126, 10.1038/nchembio.64 Volkow, 2011, Reward, dopamine and the control of food intake: implications for obesity, Trends Cogn. Sci. (Regul. Ed.), 15, 37, 10.1016/j.tics.2010.11.001 Vucetic, 2010, Central dopaminergic circuitry controlling food intake and reward: implications for the regulation of obesity, Wiley Interdiscip Rev Syst Biol Med, 2, 577, 10.1002/wsbm.77 Wren, 2001, Ghrelin enhances appetite and increases food intake in humans, J. Clin. Endocrinol. Metab., 86, 5992, 10.1210/jcem.86.12.8111