Structures And Pharmacology Of Orexin Receptors

Initially, we used an orphan GPCR termed HFGAN72 (which now named as orexin-1 receptor, OX1R or hcrtrl to identify orexins. Since we found that orexin B has significaltly lower affinity for the human (OX1R), we sought other orexin receptors for which orexin B has high affinity. A BLAST search of the dbEST database with the OX1R amino acid sequence detected another orexin receptor, orexin-2 receptor OX2R, or hcrtr2.2 The actions of orexins are mediated by these two receptors.2 Among various classes of G protein-coupled receptors, OX1R is structurally more similar to certain neuropeptide receptors, most notably to the Y2 Neuropeptide Y (NPY) receptor (26% similarity), followed by the thyrotropin-releasing hormone (TRH) receptor, cholesystokinin type-A receptor and NK2 neurokinin receptor (25 % 23% and 20% similarity, respectively).

The amino acid identity between the deduced full-length human OX1R and OX2R sequences is 64%. Thus, these receptors are much more similar to each other than they are to other GPCRs. Amino acid identities between the human and rat homologues of each of these receptors are 94% for OX1R and 95% for OX2R, indicating that both receptor genes are highly conserved between the species. Competitive radioligand binding assays using CHO cells expressing OX1R suggested that orexin A is a high-affinity agonist for OX1R. The concentration of cold orexin A required to displace 50% of specific radioligand binding (IC50) was 20 nM. Human orexin B also acted as a specific agonist on OX1R. However, human orexin B has significantly lower affinity compared to human OX1R: the calculated IC50 in competitive binding assay was 250 nM for human orexin B, indicating 2 orders of magnitude lower affinity as compared with orexin. A (Fig 2).

On the other hand, binding experiments using CHO cells expressing the human OX2R cDNA demonstrated that OX2R is a high affinity receptor for human orexin B with IC50 of 20 nM. Orexin A also had high affinity for this receptor with IC50 of 20 nM, which is similar to the value for orexin B, suggesting that OX2R is a non-selective receptor for both orexin A and orexin B (Fig 2).

Orexin Structure

Figure 2. Schematic representation of orexin system. Orexin-A and orexin-B are derived from a common precursor peptide, prepro-orexin. The actions of orexins are mediated via two G protein-coupled receptors named orexin-1 (OX1R) and orexin-2 (OX2R) receptors. OX1R is selective for orexin-A, whereas OX2R is a nonselective receptor for both orexin-A and orexin-B.

Figure 2. Schematic representation of orexin system. Orexin-A and orexin-B are derived from a common precursor peptide, prepro-orexin. The actions of orexins are mediated via two G protein-coupled receptors named orexin-1 (OX1R) and orexin-2 (OX2R) receptors. OX1R is selective for orexin-A, whereas OX2R is a nonselective receptor for both orexin-A and orexin-B.

Was this article helpful?

0 0
Natural Cures For Insomnia

Natural Cures For Insomnia

How Would You Love To Finally Get A Decent Night's Sleep? Do you toss and turn all night long without getting much of a wink of sleep? Are you tired of counting sheep for hours without falling asleep? Wouldn't you love to be able to fall asleep simply, easily and naturally, without pills, potions or harmful medicine?

Get My Free Ebook


Post a comment