TY - JOUR T1 - Transposition of Three Amino Acids Transforms the Human Metabotropic Glutamate Receptor (mGluR)-3-Positive Allosteric Modulation Site to mGluR2, and Additional Characterization of the mGluR2-Positive Allosteric Modulation Site JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 240 LP - 251 DO - 10.1124/jpet.108.138271 VL - 326 IS - 1 AU - Blake A. Rowe AU - Hervé Schaffhauser AU - Sylvia Morales AU - Laura S. Lubbers AU - Celine Bonnefous AU - Theodore M. Kamenecka AU - Jeffrey McQuiston AU - Lorrie P. Daggett Y1 - 2008/07/01 UR - http://jpet.aspetjournals.org/content/326/1/240.abstract N2 - Glutamate is a major neurotransmitter in the central nervous system, and abnormal glutamate neurotransmission has been implicated in many neurological disorders, including schizophrenia, Alzheimer's disease, Parkinson's disease, addiction, anxiety, depression, epilepsy, and pain. Metabotropic glutamate receptors (mGluRs) activate intracellular signaling cascades in a G protein-dependent manner, which offer the opportunity for developing drugs that regulate glutamate neurotransmission in a functionally selective manner. In the present study, we further characterize the human mGluR2 (hmGluR2) potentiator binding site by showing that the substitution of the three amino acids found to be required for hmGluR2 potentiation, specifically Ser688, Gly689, and Asn735, with the homologous hmGluR3 amino acids, inactivates the positive allosteric modulator activity of several structurally unique mGluR2 potentiators. Based on the characterization of the hmGluR2 potentiator binding site, we developed a novel scintillation proximity assay that was able to discriminate between compounds that were hmGluR2-specific potentiators, and those that were active on both hmGluR2 and hmGluR3. In addition, we substituted Ser688, Gly689, and Asn735 into hmGluR3 and created an active hmGluR2 allosteric modulation site on the hmGluR3 receptor. The American Society for Pharmacology and Experimental Therapeutics ER -