Meye, F. J., Ramakers, G. M. & Adan, R. A. The vital role of constitutive GPCR activity in the mesolimbic dopamine system. Transl. Psychiatry 4, e361 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sando, R. & Sudhof, T. C. Latrophilin GPCR signaling mediates synapse formation. eLife https://doi.org/10.7554/eLife.65717 (2021).

Xiao, X. et al. A new understanding of GHSR1a—independent of ghrelin activation. Ageing Res Rev. 64, 101187 (2020).

Article  CAS  PubMed  Google Scholar 

Tao, Y. X. Constitutive activation of G protein-coupled receptors and diseases: insights into mechanisms of activation and therapeutics. Pharmacol. Ther. 120, 129–148 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bond, R. A. & Ijzerman, A. P. Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery. Trends Pharmacol. Sci. 27, 92–96 (2006).

Article  CAS  PubMed  Google Scholar 

Zhang, D. L. et al. Gq activity- and β-arrestin-1 scaffolding-mediated ADGRG2/CFTR coupling are required for male fertility. eLife https://doi.org/10.7554/eLife.33432 (2018).

Yao, Y. et al. A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. eLife https://doi.org/10.7554/eLife.05449 (2015).

Audo, I. et al. Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness. Am. J. Hum. Genet 90, 321–330 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Watkins, L. R. & Orlandi, C. In vitro profiling of orphan G protein coupled receptor (GPCR) constitutive activity. Br. J. Pharmacol. https://doi.org/10.1111/bph.15468 (2021).

Article  PubMed  Google Scholar 

Wacker, D., Stevens, R. C. & Roth, B. L. How ligands illuminate GPCR molecular pharmacology. Cell 170, 414–427 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Abboud, D. et al. GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11. Nat. Commun. 11, 4752 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bates, B. et al. Characterization of Gpr101 expression and G-protein coupling selectivity. Brain Res. 1087, 1–14 (2006).

Article  CAS  PubMed  Google Scholar 

Nilaweera, K. N. et al. G protein-coupled receptor 101 mRNA expression in the mouse brain: altered expression in the posterior hypothalamus and amygdala by energetic challenges. J. Neuroendocrinol. 19, 34–45 (2007).

Article  CAS  PubMed  Google Scholar 

Trivellin, G., Faucz, F. R., Daly, A. F., Beckers, A. & Stratakis, C. A. Hereditary endocrine tumours: current state-of-the-art and research opportunities: GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis. Endocr. Relat. Cancer 27, T87–T97 (2020).

Article  CAS  PubMed  Google Scholar 

Hou, Z. S. & Tao, Y. X. Mutations in GPR101 as a potential cause of X-linked acrogigantism and acromegaly. Prog. Mol. Biol. Transl. Sci. 161, 47–67 (2019).

Article  CAS  PubMed  Google Scholar 

Trivellin, G. et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N. Engl. J. Med. 371, 2363–2374 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Melmed, S. Pathogenesis and diagnosis of growth hormone deficiency in adults. N. Engl. J. Med. 380, 2551–2562 (2019).

Article  CAS  PubMed  Google Scholar 

Trivellin, G. et al. The X-linked acrogigantism-associated gene gpr101 is a regulator of early embryonic development and growth in zebrafish. Mol. Cell. Endocrinol. 520, 111091 (2021).

Article  CAS  PubMed  Google Scholar 

Yao, X. et al. Coupling ligand structure to specific conformational switches in the β2-adrenoceptor. Nat. Chem. Biol. 2, 417–422 (2006).

Article  CAS  PubMed  Google Scholar 

Yang, D. et al. Allosteric modulation of the catalytic VYD loop in Slingshot by its N-terminal domain underlies both Slingshot auto-inhibition and activation. J. Biol. Chem. 293, 16226–16241 (2018).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Suomivuori, C. M. et al. Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor. Science 367, 881–887 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wingler, L. M. et al. Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR. Science 367, 888 (2020).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Veldhuis, J. D. Changes in pituitary function with ageing and implications for patient care. Nat. Rev. Endocrinol. 9, 205–215 (2013).

Article  CAS  PubMed  PubMed Central  Google Scholar 

van den Beld, A. W. et al. The physiology of endocrine systems with ageing. Lancet Diabetes Endocrinol. 6, 647–658 (2018).

Article  PubMed  PubMed Central  Google Scholar 

Savino, W., Mendes-da-Cruz, D. A., Lepletier, A. & Dardenne, M. Hormonal control of T-cell development in health and disease. Nat. Rev. Endocrinol. 12, 77–89 (2016).

Article  CAS  PubMed  Google Scholar 

Savino, W. & Dardenne, M. Pleiotropic modulation of thymic functions by growth hormone: from physiology to therapy. Curr. Opin. Pharmacol. 10, 434–442 (2010).

Article  CAS  PubMed  Google Scholar 

Yang, F. et al. Structural basis of GPBAR activation and bile acid recognition. Nature 587, 499–504 (2020).

Article  CAS  PubMed  Google Scholar 

Lu, J. et al. Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat. Struct. Mol. Biol. 24, 570–577 (2017).

Article  CAS  PubMed  Google Scholar 

Giordano, R., Bonelli, L., Marinazzo, E., Ghigo, E. & Arvat, E. Growth hormone treatment in human ageing: benefits and risks. Hormones 7, 133–139 (2008).

Article  PubMed  Google Scholar 

Qu, C. et al. Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E2 receptor EP2 subtype. Sci. Adv. https://doi.org/10.1126/sciadv.abf1268 (2021).

Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mindell, J. A. & Grigorieff, N. Accurate determination of local defocus and specimen tilt in electron microscopy. J. Struct. Biol. 142, 334–347 (2003).

Article  PubMed  Google Scholar 

Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife https://doi.org/10.7554/eLife.42166 (2018).

Kucukelbir, A., Sigworth, F. J. & Tagare, H. D. Quantifying the local resolution of cryo-EM density maps. Nat. Methods 11, 63–65 (2014).

Article  CAS  PubMed  Google Scholar 

Scheres, S. H. & Chen, S. Prevention of overfitting in cryo-EM structure determination. Nat. Methods 9, 853–854 (2012).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D 66, 213–221 (2010).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yang, F. et al. Structure, function and pharmacology of human itch receptor complexes. Nature 600, 164–169 (2021).

Article  CAS  PubMed  Google Scholar 

Cheng, J. et al. Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism. Cell Metab. 34, 240–255 e210 (2022).

Article  CAS  PubMed  Google Scholar 

Li, A. et al. Discovery of novel FFA4 (GPR120) receptor agonists with β-arrestin2-biased characteristics. Future Med Chem. 7, 2429–2437 (2015).

Article  CAS  PubMed