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 presen t 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 t he 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 hig her binding capacity of the nanomolar binding mode. Signal transductio n was not induced by ZnCl2 but 10 mu M ZnCl2 enhanced the effect of ne urokinin B. Ala-substitution of HisV:Ol eliminated the enhancing effec t of Zn2+ on peptide binding. It is concluded that physiological conce ntrations 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.