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 125I-[MePhe7]neurokinin B to 150%. [MePhe7]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 microM ZnCl2 enhanced the effect of neurokinin B. Ala-substitution of HisV:01 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.
Rosenkilde
M M
MM
Department of Pharmacology, The Panum Institute 18.6, Copenhagen, Denmark.
Lucibello
M
M
Holst
B
B
Schwartz
T W
TW
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D019556:COS Cells; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D009154:Mutation; D015287:Neurokinin B / Q000494:pharmacology*; D011487:Protein Conformation; D018039:Receptors, Tachykinin / Q000819:agonists* / Q000737:chemistry* / Q000235:genetics; D015032:Zinc / Q000737:chemistry*
D008565:Membrane Proteins; D018039:Receptors, Tachykinin; D006639:Histidine; D015287:Neurokinin B; D015032:Zinc