Molecular evolution of neuropeptide receptors with regard to maintaining high affinity to their authentic ligands

Hyun Ju Cho, Sujata Acharjee, Mi Jin Moon, Da Young Oh, Hubert Vaudry, Hyuk Bang Kwon, Jae Young Seong

Research output: Contribution to journalShort surveypeer-review

32 Citations (Scopus)


Recently, we cloned many of the bullfrog neuropeptide G protein-coupled receptors (GPCRs), including receptors for vasotocin (VT), mesotocin, gonadotropin-releasing hormone (GnRH), neurotensin, apelin, and metastin. Bullfrog GPCRs usually have high affinity for bullfrog ligands but relatively low affinity for mammalian ligands. Reciprocally, synthetic agonists and antagonists developed based upon mammalian ligands display lower affinity at bullfrog receptors. Studies using chimeric or domain-swapped receptors indicate that the motifs responsible for differential ligand selectivity usually reside within transmembrane domain 6 (TMD6)-extracellular loop 3 (ECL3)-transmembrane domain 7 (TMD7). Triple mutation of mammalian V1aR (Phe6.51 to Tyr, Ile6.53 to Thr, and Pro7.33 to Thr) increases VT affinity but greatly reduces arginine vasopressin affinity. This binding profile is similar to that of bullfrog VT1R. Changing just three amino acids in the bullfrog GnRH receptor-1 (i.e. Ser-Gln-Ser in the ECL3) to those found in the type-I mammalian GnRH receptor (i.e. Ser-Glu-Pro) reverses GnRH selectivity. In conclusion, specific receptor motifs that govern ligand selectivity can be determined by comparative molecular analyses of GPCRs and their ligands. Such analysis provides clues for understanding how GPCRs maintain high affinity to their authentic ligands.

Original languageEnglish
Pages (from-to)98-107
Number of pages10
JournalGeneral and Comparative Endocrinology
Issue number1-3
Publication statusPublished - 2007

Bibliographical note

Funding Information:
This work was supported by a Grant (KRF-2004-C00141) to H.B.K. from the Korea Research Foundation and a Grant (M103KV010005-06K2201-00510) to J.Y.S. from Brain Research Center of the 21st Century Frontier Research Program.


  • Coevolution
  • G protein-coupled receptors
  • Ligand selectivity
  • Neuropeptides

ASJC Scopus subject areas

  • Animal Science and Zoology
  • Endocrinology


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