Orexin/hypocretin receptor chimaeras reveal structural features important for orexin peptide distinction

FEBS Lett. 2011 May 6;585(9):1368-74. doi: 10.1016/j.febslet.2011.04.020. Epub 2011 Apr 15.


We wanted to analyze the basis for the distinction between OX(1) and OX(2) orexin receptors by the known agonists, orexin-A, orexin-B and Ala(11), D-Leu(15)-orexin-B, of which the latter two show some selectivity for OX(2). For this, chimaeric OX(1)/OX(2) and OX(2)/OX(1) orexin receptors were generated. The receptors were transiently expressed in HEK-293 cells, and potencies of the agonists to elicit cytosolic Ca(2+) elevation were measured. The results show that the N-terminal regions of the receptor are most important, and the exchange of the area from the C-terminal part of the transmembrane helix 2 to the transmembrane helix 4 is enough to lead to an almost total change of the receptor's ligand profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites / genetics
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / pharmacology*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Neuropeptides / chemistry
  • Neuropeptides / pharmacology*
  • Orexin Receptors
  • Orexins
  • Protein Isoforms / agonists
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Structure, Secondary
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, Neuropeptide / agonists*
  • Receptors, Neuropeptide / chemistry
  • Receptors, Neuropeptide / genetics
  • Recombinant Fusion Proteins / agonists*
  • Recombinant Fusion Proteins / chemistry


  • HCRT protein, human
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Protein Isoforms
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Recombinant Fusion Proteins