title: Selective metabotropic receptor agonists distinguish non-ionotropic glutamate binding sites.
abstract: Metabotropic glutamate receptors (mGluRs) are thought to mediate diverse processes in brain including synaptic plasticity and excitotoxicity. These receptors are often divided into three groups by their pharmacological profiles. [3H]Glutamate binding in the presence of compounds selective for ionotropic glutamate receptors can be used as a general assay for these receptors; subtypes of this non-ionotropic [3H]glutamate binding differ in both pharmacology and anatomical distribution, and are differentially sensitive to quisqualate. The characteristics of these binding sites are consistent with those of group 1 (high-affinity quisqualate) and group 2 (low-affinity quisqualate) mGluRs. Under our assay conditions, no [3H]glutamate binding to group 3-like (L-AP4 sensitive) sites could be demonstrated. We have attempted to characterize particular agents which may selectively measure [3H]glutamate binding to mGluR subtypes. We used two isomers of 2-(carboxycyclopropyl)glycine, L-CCG-I and L-CCG-II, and the (2S,1'R,2'R,3'R) isomer of 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) as competitors of non-ionotropic [3H]glutamate binding sites. DCG-IV clearly distinguishes two binding sites. Quantitative levels of DCG-IV binding by anatomic region correlate with quisqualate-defined binding subtypes: high-affinity DCG-IV binding correlates with low-affinity quisqualate binding, whereas low-affinity DCG-IV binding correlates with high-affinity quisqualate binding. L-CCG-II displaces only one type of non-ionotropic [3H]glutamate binding, corresponding to high-affinity quisqualate binding. Therefore DCG-IV and L-CCG-II at appropriate concentrations appear to distinguish binding to putative group 2 vs. group 1 mGluRs. L-CCG-I displaces both high- and low-affinity quisqualate binding sites, but unlike the other two compounds, does not clearly distinguish between them.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston 02114, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Testa
authors.forename: Z R
authors.initials: ZR
authors.lastname: Hollingsworth
authors.forename: H
authors.initials: H
authors.lastname: Shinozaki
authors.forename: J B
authors.initials: JB
authors.lastname: Penney
authors.forename: A B
authors.initials: AB
authors.lastname: Young
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001667:Binding, Competitive; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D016318:Quisqualic Acid / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D013237:Stereoisomerism; D014316:Tritium
chemical_list: D000600:Amino Acids, Dicarboxylic; D018690:Excitatory Amino Acid Agonists; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; D014316:Tritium; C035261:(alpha-carboxycyclopropyl)glycine; D018698:Glutamic Acid; D016318:Quisqualic Acid