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

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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 HisVI‐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 HisVI‐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 HisVI‐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.