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Distribution and abundance of metabotropic glutamate receptor subtype 2 in rat brain revealed by [ 3 H]LY354740 binding in vitro and quantitative radioautography: Correlation with the sites of synthesis, expression, and agonist stimulation of [ 35 S]GTPγs binding
Author(s) -
Richards Grayson,
Messer Jürg,
Malherbe Pari,
Pink Richard,
Brockhaus Manfred,
Stadler Heinz,
Wichmann Jürgen,
Schaffhauser Hervé,
Mutel Vincent
Publication year - 2005
Publication title -
journal of comparative neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.855
H-Index - 209
eISSN - 1096-9861
pISSN - 0021-9967
DOI - 10.1002/cne.20538
Subject(s) - metabotropic receptor , agonist , receptor , biology , metabotropic glutamate receptor , glutamate receptor , in situ hybridization , microbiology and biotechnology , biochemistry , messenger rna , gene
Until recently, there was a lack of selective radioligands for the subtypes of metabotropic glutamate (mGlu) receptors. [ 3 H]LY354740 ((+)‐2‐aminobicyclo[3,1,0]hexane‐2,6‐dicarboxylic acid), a selective agonist for group II receptors (mGlu2 and ‐3, which are negatively coupled to cAMP production), has now been used to map their brain distribution and abundance by in vitro binding and quantitative radioautography. The selective cation dependence of its binding allowed the discrimination between mGlu2 and mGlu3 receptor labeling. Thus, in the presence of Ca 2+ and Mg 2+ ions, the agonist bound selectively to mGlu2 receptors as evidenced by: 1) the correlative distribution and abundance of binding sites (highest in the lacunosum moleculare of the hippocampus and lowest in white matter) with mGlu2 receptor mRNA and protein revealed by in situ hybridization histochemistry and immunohistochemistry, respectively; 2) its selective pharmacology; and 3) the distribution of LY354740‐stimulated [ 35 S]GTPγS binding (25–97% above basal, according to the brain region), revealing G protein‐coupled receptor coupling to G i proteins. Nonspecific binding (in the presence of 10 μM DCG‐IV, a group II‐selective, mGlu2‐preferring, receptor agonist) was <10% of total. In adjacent sections, the distribution of binding sites for [ 3 H]DCG‐IV was very similar. This extensive study paves the way for investigations of the regional expression and regulation of mGlu2 receptors in human CNS diseases, such as Alzheimer's disease, which may reveal their functional roles and identify potential therapeutic drug targets. Indeed, it has recently been demonstrated (Higgins et al. [2004] Neuropharmacology 46:907–917) that pharmacological manipulation of mGlu2 receptors influences cognitive performance in the rodent. J. Comp. Neurol. 487:15–27, 2005. © 2005 Wiley‐Liss, Inc.