Conserved HisVI‐17 of the NK‐1 receptor is involved in binding of non‐peptide antagonists but not substance P

Abstract

Residue number 17 in transmembrane segment VI has been shown to be crucial for the binding of agonists in G‐protein‐coupled receptors for the monoamines. In many peptide receptors a histidyl residue has been conserved at this position. We find that replacement of His^VI‐17 in the NK‐1 receptor with either glutamine, phenylalanine, or alanine has no apparent effect on the binding of the natural peptide ligand substance P or on the agonist induced increase in inositolphosphate turnover. However, the binding of certain non‐peptide antagonists was impaired; for example, replacement of His^VI‐17 with alanine decreased the affinity for FK888 and RP67,580 5‐ to 12‐fold, respectively. A glutamine side chain was a good substitute for the imidazole in the binding of all non‐peptide antagonists. It is concluded that the conserved His^VI‐17 in the NK‐1 receptor is involved in the binding of certain non‐peptide antagonists, but is not important for the action of the natural peptide agonist, substance P.