, Volume 14, Issue 1, pp 9–14 | Cite as

Growth hormone secretagogue receptor family members and ligands

  • Roy G. Smith
  • Reid Leonard
  • Alex R. T. Bailey
  • Oksana Palyha
  • Scott Feighner
  • Carina Tan
  • Karen Kulju McKee
  • Sheng-Shung Pong
  • Pat Griffin
  • Andrew Howard


We have previously reported the cloning and characterization of a new orphan G-protein-coupled receptor (GPC-R), the growth hormone secretagogue receptor (GHS-R), and shown that this receptor mediates the activity of the growth hormone-releasing peptides (GHRPs) and nonpeptide ligands such as L-692,429 and MK-0677. Because the GHS-R obviously does not belong to any of the known GPC-R subfamilies, we searched for GHS-R family members by screening a human genomic library using low-stringency hybridization and screening a Pufferfish genomic library. The Pufferfish was selected because of its compact genome. From the human genomic library, a homolog, GPR 38, with 52% identity to the GHS-R was isolated. From the Pufferfish library, three family members were isolated. The Pufferfish gene having 58% identity to the GHS-R, on expression in HEK293 cells, was activated with GHRP-6 and MK-0677. These results indicate that the GHS-R has been conserved for at least 400 million years and that the Pufferfish genome is appropriate for isolation of GHS-R family members. In our search for endogenous ligands for the orphan receptors GHS-R and GPR38, we showed that adenosine is a partial agonist of the GHS-R and that motilin is the endogenous ligand for GPR38. We also confirmed that the endogenous ligand ghrelin is a full agonist of the GHS-R.

Key Words

Growth hormone secretagogue receptor motilin adenosine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Howard, A. D., Feighner, S. D., Cully, D. F., et al. (1996). Science 273, 974–977.PubMedCrossRefGoogle Scholar
  2. 2.
    McKee, K. K., Tan, C. P., Palyha, O. C., Liu, J., Feighner, S. D., Hreniuk, D. L., Smith, R. G., Howard, A. D., and Van der Ploeg, L. H. T. (1997). Genomics 46, 426–434.PubMedCrossRefGoogle Scholar
  3. 3.
    Tan, C. P., McKee, K. K., Liu, Q., Palyha, O. C., Feighner, S. D., Hreniuk, D. L., Smith, R. G., and Howard, A. D. (1998). Genomics 52, 223–229.PubMedCrossRefGoogle Scholar
  4. 4.
    Brenner, S., Elgar, G., Sandford, R., Macrae, A., Venkatesh, B., and Aparicio, S. (1993). Nature 366, 265–268.PubMedCrossRefGoogle Scholar
  5. 5.
    Baxendale, S., Abdulla, S., Elgar, G., Buck, D., Berks, M., Micklem, G., Durbin, R., Bates, G., Brenner, S., and Beck, S. (1995). Nat. Genet. 10(1), 67–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Elgar, G., Rattray, F., Greystrong J., and Brenner, S. (1995). Genomics 27(3), 442–446.PubMedCrossRefGoogle Scholar
  7. 7.
    Mason, P. J., Stevens, D. J., Luzzatto, L., Brenner, S., and Aparicio, S. (1995). Genomics 26(3), 587–591.PubMedCrossRefGoogle Scholar
  8. 8.
    Macrae, A. D. and Brenner, S. (1995). Genomics 25(2), 436–446.PubMedCrossRefGoogle Scholar
  9. 9.
    Macrae, A. D. and Brenner, S. (1994). Genomics 24(1), 176–178.PubMedCrossRefGoogle Scholar
  10. 10.
    Palyha, O. C., Feighner, S. D., Tan, C. P., McKee, K. K., Hreniuk, D. L., Gao, Y.-D., Schleim, K. D., Yang, L., Morriello, G. J., Nargund, R., Patchett, A. A., Howard, A. D., and Smith, R. G. (2000). Mol. Endocrinol. 14(1), 160–169.PubMedCrossRefGoogle Scholar
  11. 11.
    Feighner, S. D., Howard, A. D., Prendergast, K., et al. (1998). Mol. Endocrinol. 12, 137–145.PubMedCrossRefGoogle Scholar
  12. 12.
    Cheng, K., Wei, L., Chaung, L., Chan, W. W.-S., Butler, B., and Smith, R. G. (1997). J. Endocrinol. 152, 155–158.PubMedCrossRefGoogle Scholar
  13. 13.
    Feighner, S. D., Tan, C. P., McKee, K. K., et al. (1999). Science 284, 2184–2188.PubMedCrossRefGoogle Scholar
  14. 14.
    Daikh, D. I., Douglass, J. O., and Adelman, J. P. (1989). DNA 8(8), 615–621.PubMedCrossRefGoogle Scholar
  15. 15.
    Yano, H., Seino, Y., Fujita, J., Yamada, Y., Inagaki, N., Takeda, J., Bell, G. I., Eddy, R. L., Fan, Y. S., Byers M. G., Shows, T. B., and Imura, H. (1989). FEBS Lett. 249, 248–252.PubMedCrossRefGoogle Scholar
  16. 16.
    Sakai, T., Satoh, M., Sonobe, K., Nakajima, M., Shiba, Y., and Itoh, Z. (1994). Regul. Pept. 53(3), 249–257.PubMedCrossRefGoogle Scholar
  17. 17.
    Depoortere, I., Van Assche, G., and Peeters, T. L. (1997). Brain Res. 777(1–2), 103–109.PubMedGoogle Scholar
  18. 18.
    Poitras, P., Miller, P., Dickner, M., Mao, Y. K., Daniel, E. E., St-Pierre, S., and Trudel, L. (1996). Peptides 17(4), 701–707.PubMedCrossRefGoogle Scholar
  19. 19.
    Peeters, T. L., Bormans, V., and Vantrappen, G. (1988). Regul. Pept. 23(2), 171–182.PubMedCrossRefGoogle Scholar
  20. 20.
    Depoortere, I., Peeters, T. L., and Vantrappen, G. (1991). Peptides 12(1), 89–94.PubMedCrossRefGoogle Scholar
  21. 21.
    Depoortere, I., Peeters, T. L,, and Vantrappen, G. (1993). Peptides 14(6), 1153–1157.PubMedCrossRefGoogle Scholar
  22. 22.
    Depoortere, I. and Peeters, T. L. (1997). Am. J. Physiol. 272(5 Pt1), G994-G999.PubMedGoogle Scholar
  23. 23.
    Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., and Kangawa, K. (1999). Nature 402(6762), 656–660.PubMedCrossRefGoogle Scholar
  24. 24.
    Murphy, D., Si-Hoe, S.-L., Brenner, S., and Venkatesh, B. (1998). BioEssays 20, 741–749.PubMedCrossRefGoogle Scholar
  25. 25.
    Guan, X.-M., Yu, H., Palyha, O. C., McKee, K. K., Feighner, S. D., Sirinathsinghji, D. J. S., Smith, R. G., Van der Ploeg, L. H. T., and Howard, A. D. (1997). Mol. Brain Res. 48, 23–29.PubMedCrossRefGoogle Scholar
  26. 26.
    DeGennaro Colonna, V., Rossoni, G., Beruareggi, M., Muller, E. E., and Berti, F. (1997). Cardiologia, 42(11), 1165–1172.Google Scholar
  27. 27.
    Rossoni, G., De Gennaro Colonna, V., Bernareggi, M., Polvani, G. L., Muller, E. E., and Berti, F. (1998). J. Cardiovasc. Pharmacol. 32(2), 260–265.PubMedCrossRefGoogle Scholar
  28. 28.
    Rossoni, G., Locatelli, V., De Gennaro Colonna, V., Torsello, A., Schweiger, F., Boghen, M., Nilsson, M., Bernareggi, M., Muller, E. E., and Berti, F. (1999). J. Cardiovasc. Pharmacol. 34(3), 454–460.PubMedCrossRefGoogle Scholar
  29. 29.
    Bisi, G., Podio, V., Valetto, M. R., Broglio, F., Bertuccio, G., Aimaretti, G., Pelosi, E., Del Rio, G., Muccioli, G., Ong, H., Boghen, M. F., Deghenghi, R., and Ghigo E. (1999). Eur. J. Pharmacol. 381(1), 31–38.PubMedCrossRefGoogle Scholar
  30. 30.
    Locatelli, V., Rossoni, G., Schweiger, F., Torsello, A., de Gennaro Colonna, V., Bernareggi, M., Deghenghi, R., Muller, E. E., and Berti, F. (1999). Endocrinology 140, 4024–4031.PubMedCrossRefGoogle Scholar
  31. 31.
    Tivesten, A., Bollano, E., Caidahl, K., Kujacic, V., Sun, X. Y., Hedner, T., Hjalmarson, A., Bengtsson, B. A., and Isgaard, J. (2000). Endocrinology 141(1), 60–66.PubMedCrossRefGoogle Scholar
  32. 32.
    Premont, J., Perez, M., and Bockaert, J. (1977). Mol. Pharmacol. 13, 662–670.PubMedGoogle Scholar
  33. 33.
    Ferre, S., Fredholm, B. B., Morelli, M., Popoli, P., and Fuxe, K. (1997). TINS 20(10), 482–487.PubMedGoogle Scholar
  34. 34.
    Ongini, E. and Fredholm, B. B. (1996). Trends Pharmacol. Sci. 17, 364–372.PubMedCrossRefGoogle Scholar
  35. 35.
    Porter, J. C., Kedzierski, W., Aguila-Mansilla, N., and Jorquera, B. A. (1990). Endocrinology 126, 2474–2481.PubMedCrossRefGoogle Scholar
  36. 36.
    Porter, J. C., Aguila-Mansilla, N., Ramin, S. M., Kozlowski, G. P., and Kedzierski, W. (1991). Endocrinology 129, 2477–2485.PubMedGoogle Scholar
  37. 37.
    Porter, J. C., Ijames, C. F., Wang, T.-C L., and Markey, S. P. (1995). Proc. Natl. Acad. Sci. USA 92, 5351–5355.PubMedCrossRefGoogle Scholar
  38. 38.
    Smith R. G., Feighner, S., Prendergast, K., Guan, X., and Howard, A. (1999). Trends Endocrinol. Metab. 10(4), 128–135.CrossRefPubMedGoogle Scholar
  39. 39.
    Smith, R. G., Griffin, P. R., Xu, Y., et al. (2000). Adenosine: a partial agonist of the growth hormone secretagogue receptor. Biochem. Biophys. Res. Commun. 276(3), 1306–1313.PubMedCrossRefGoogle Scholar
  40. 40.
    Tullin, S., Hansen, B. S., Ankersen, M., Moller, J., Von Cappelen, K. A. and Thim, L. (2000) Adenosine is an agonist of the growth hormone secretagogue receptor. Endocrinology 141(9), 3397–3402.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2001

Authors and Affiliations

  • Roy G. Smith
    • 1
    • 2
  • Reid Leonard
    • 2
  • Alex R. T. Bailey
    • 1
  • Oksana Palyha
    • 2
  • Scott Feighner
    • 2
  • Carina Tan
    • 2
  • Karen Kulju McKee
    • 2
  • Sheng-Shung Pong
    • 2
  • Pat Griffin
    • 2
  • Andrew Howard
    • 2
  1. 1.Huffington Center on Aging and Department of Molecular and Cellular BiologyBaylor College of MedicineHouston
  2. 2.Merck Research LaboratoriesRahway

Personalised recommendations