The quest for novel bioactive peptides utilizing orphan seven-transmembrane-domain receptors

J Mol Med (Berl). 1999 Jun;77(6):495-504. doi: 10.1007/s001090050403.


Various sorts of bioactive molecules including hormones, neurotransmitters, and chemokines transmit signals into cells by binding to so-called seven-transmembrane-domain receptors (7TMRs). The recent progress in cDNA and genome DNA analyses has brought the discovery of numerous genes encoding ligand-unknown "orphan" 7TMRs. We have developed a strategy to identify the ligands of orphan 7TMRs by monitoring specific signal transductions induced in cells expressing orphan 7TMRs. Employing this method, we succeeded in identifying the natural ligands of the orphan 7TMRs, hGR3, and APJ. The ligand peptide identified for hGR3 was found to show a specific prolactin release promoting activity in rat anterior pituitary cells in in vitro culture and was therefore named "prolactin-releasing peptide." We named another novel bioactive peptide "apelin," for "APJ endogenous ligand." Although the biological functions of apelin are still under investigation, APJ reportedly acts as a coreceptor in the process of human immunodeficiency virus infection. We believe that the identification of orphan 7TMR ligands will provide clues to reveal the unknown regulatory mechanisms of various physiological phenomena and opportunities for novel drug discovery in the future.

Publication types

  • Review

MeSH terms

  • Animals
  • Apelin
  • Carrier Proteins / isolation & purification*
  • Carrier Proteins / metabolism
  • Humans
  • Hypothalamic Hormones / isolation & purification*
  • Hypothalamic Hormones / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Molecular Sequence Data
  • Neuropeptides / isolation & purification*
  • Neuropeptides / metabolism
  • Prolactin-Releasing Hormone
  • Receptors, Cell Surface / agonists*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / isolation & purification*
  • Sequence Alignment


  • APLN protein, human
  • Apelin
  • Apln protein, rat
  • Carrier Proteins
  • Hypothalamic Hormones
  • Intercellular Signaling Peptides and Proteins
  • Ligands
  • Neuropeptides
  • PRLH protein, human
  • Prlh protein, rat
  • Prolactin-Releasing Hormone
  • Receptors, Cell Surface