Metabotropic glutamate receptor 1

The glutamate receptor, metabotropic 1, also known as GRM1, is a human is_associated_with::gene which encodes the metabotropic glutamate receptor 1 (mGluR1) protein.

Function
L-is_associated_with::glutamate is the major excitatory is_associated_with::neurotransmitter in the central nervous system and activates both ionotropic and metabotropic is_associated_with::glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of is_associated_with::G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the is_associated_with::cyclic AMP cascade but differ in their agonist selectivities. Alternative splice variants of the GRM1 gene have been described but their full-length nature has not been determined.

Studies with knockout mice
Mice lacking functional glutamate receptor 1 were reported in 1994. By is_associated_with::homologous recombination mediated gene targeting those mice became deficient in mGlu receptor 1 protein. The mice did not show any basic anatomical changes in the brain but had impaired cerebellar is_associated_with::long-term depression and hippocampal is_associated_with::long-term potentiation. In addition they had impaired motor functions, characterized by impaired balance. In the is_associated_with::Morris watermaze test, an assay for learning abilities, those mice needed significantly more time to successfully complete the task.

Clinical significance
Mutations in the GRM1 gene may contribute to is_associated_with::melanoma susceptibility.

Ligands
In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct is_associated_with::allosteric is_associated_with::binding sites exist on the mGluR1. A respectable number of potent and specific allosteric ligands – predominantly antagonists/inhibitors – has been developed in recent years, although no orthosteric subtype-selective ligands have yet been discovered (2008).


 * JNJ-16259685: highly potent, selective non-competitive antagonist
 * R-214,127 and [3H]-analog: high-affinity, selective allosteric inhibitor
 * YM-202,074: high-affinity, selective allosteric antagonist
 * YM-230,888: high-affinity, selective allosteric antagonist
 * YM-298,198 and [3H]-analog: selective non-competitive antagonist
 * FTIDC: highly potent and selective allosteric antagonist/inverse agonist
 * A-841,720: potent non-competitive antagonist; minor hmGluR5 binding
 * VU-71: potentiator
 * Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides: orally available PAMs