Opposite effects of Zn on the in vitro binding of [3H]LY354740 to recombinant and native metabotropic glutamate 2 and 3 receptors.
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 IC(50) values for the high- and low-affinity components of 60 +/- 10 microM and 2 +/- 0.7 mM, respectively. Zn induced a complex biphasic effect of inhibition and enhancement of [(3)H]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 microm 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 microM 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.
Malherbe
Pari
P
Pharma Division, Discovery Research CNS, F. Hoffmann-La Roche Ltd, Basel, Switzerland. parichehr.malherbe@roche.com
Richards
J Grayson
JG
Broger
Clemens
C
Zenner
Marie-Thérèse
MT
Messer
Jürg
J
Kratzeisen
Claudia
C
Nakanishi
Shigetada
S
Mutel
Vincent
V
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D002460:Cell Line; D002712:Chlorides / Q000737:chemistry* / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014316:Tritium / Q000378:metabolism; D017967:Zinc Compounds / Q000737:chemistry*
D001643:Bridged Bicyclo Compounds; D002712:Chlorides; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D017967:Zinc Compounds; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D014316:Tritium; C016837:zinc chloride; C104753:eglumetad