Opposite effects of Zn on the in vitro binding of [3H]LY354740 to recombinant and native metabotropic glutamate 2 and 3 receptors

• Published in: Journal of neurochemistry Vol. 94; no. 1; pp. 150 - 160
• Main Authors: Malherbe, Pari, Richards, J. Grayson, Broger, Clemens, Zenner, Marie‐Thérèse, Messer, Jürg, Kratzeisen, Claudia, Nakanishi, Shigetada, Mutel, Vincent
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.07.2005; Blackwell; Blackwell Publishing Ltd
• Subjects: Amino Acid Sequence; Animals; Binding Sites - genetics; Biochemistry; Biological and medical sciences; Brain; Bridged Bicyclo Compounds - metabolism; Cell Line; Cell receptors; Cell structures and functions; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Chlorides - chemistry; Chlorides - physiology; Excitatory Amino Acid Agonists - metabolism; Fundamental and applied biological sciences. Psychology; Humans; knockout; metabotropic glutamate receptor; Mice; Mice, Knockout; Molecular and cellular biology; Molecular Sequence Data; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); mutagenesis/chimeric approaches; Neurology; Point Mutation; Protein Binding - genetics; Rats; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; receptor‐binding studies; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rodents; Tritium - metabolism; Vertebrates: nervous system and sense organs; Zinc; Zinc Compounds - chemistry; Zn effect; knockout; Zn effect; metabotropic glutamate receptor; Rodentia; Central nervous system; Glutamate receptor; In vitro; mglu2 glutamate receptor; mglu3 glutamate receptor; Section; Group II mglu glutamate receptor; Zinc; Encephalon; Vertebrata; Mammalia; Mutagenesis; Metabotropic receptor; Mouse; receptor-binding studies; mutagenesis/chimeric approaches; Hippocampus; Biological receptor
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03176.x

We investigated the effect of Zn on agonist binding to both recombinant and native mGlu2 and mGlu3 receptors. Zn had a biphasic inhibitory effect on recombinant mGlu2 with IC50 values for the high‐ and low‐affinity components of 60 ± 10 µm and 2 ± 0.7 mm, respectively. Zn induced a complex biphasic effect of inhibition and enhancement of [3H]LY354740 binding to mGlu3. Observations with a series of chimeric mGlu2/3 receptors suggest that the Zn effect resides in the N‐terminal domain of mGlu2 and mGlu3. We observed that the His56 of mGlu2, which corresponds to Asp63 in mGlu3 was largely accountable for the second phase of the Zn effect. As revealed by quantitative receptor radioautography, the addition of up to 100 µm Zn to brain sections of wild‐type mice resulted in significant decreases in binding density in most brain regions. In particular, the mid‐molecular layer of the dentate gyrus (DGmol) and the CA1 lacunosum moleculare of hippocampus (CA1‐LMol) showed reductions of 62 and 67%, respectively. In contrast, the addition of 300 µm Zn to brain sections of mGlu2–/– mice caused large increases in binding density of 289 and 242% in DGmol and CA1‐LMol, respectively. Therefore, Zn might play a role as a physiological modulator of group II mGlu receptor function.