Natural agonist enhancing bis-His zinc-site in transmembrane segment V of the tachykinin NK3 receptor

In the wild-type tachykinin NK3A receptor histidyl residues are present at two positions in TM-V, V:01 and V:05, at which Zn2+ functions as an antagonist in NK1 and kappa-opioid receptors with engineered metal-ion sites, Surprisingly, in the NK3A receptor Zn2+ instead increased the binding of the agonist I-125-[MePhe(7)]neurokinin B to 150%. [MePhe(7)]neurokinin B bound to the NK3A receptor in a two-component mode of which Zn2+ eliminated the subnanomolar binding mode but induced a higher binding capacity of the nanomolar binding mode. Signal transduction was not induced by ZnCl2 but 10 mu M ZnCl2 enhanced the effect of neurokinin B. Ala-substitution of HisV:Ol eliminated the enhancing effect of Zn2+ on peptide binding. It is concluded that physiological concentrations of Zn2+ have a positive modulatory effect on the binding and function of neurokinin B on the NK3A receptor through a bis-His site in TM-V, (C) 1998 Federation of European Biochemical Societies.