The glutamate receptor, metabotropic 1, also known as GRM1, is a human

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

which encodes the metabotropic glutamate receptor 1 (mGluR1) protein.

Function

L-

glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

is the major excitatory

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neu ...

in the central nervous system and activates both

ionotropic Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...

and

metabotropic A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: met ...

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...

s. 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

G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I, which includes GRM1 alongside GRM5, have been shown to activate

phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...

. 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

cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal tra ...

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. A possible connection has been suggested between mGluRs and neuromodulators, as mGluR1 antagonists block

adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like bet ...

activation in neurons.

Studies with knockout mice

Mice lacking functional glutamate receptor 1 were reported in 1994. By

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...

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

long-term depression In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depend ...

and hippocampal

long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...

. In addition they had impaired motor functions, characterized by impaired balance. In the

Morris watermaze The Morris water navigation task, also known as the Morris water maze (not to be confused with '' water maze''), is a behavioral procedure mostly used with rodents. It is widely used in behavioral neuroscience to study spatial learning and me ...

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

melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...

susceptibility. Antibodies against mGluR1 receptors cause

cerebellar ataxia Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias. Cerebellar ataxia can occur as a result of many diseases and may present with sympto ...

and impair long-term depression (LTDpathies) in the cerebellum.

Ligands

In addition to the orthosteric site (the site where the endogenous ligand glutamate binds) at least two distinct

allosteric In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric sit ...

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

s 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 sup>3Hanalog: 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 sup>3Hanalog: 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 9''H''-xanthene-9-carboxylic acid oxazol-2-yl-amides: orally available PAMs * Cyclothiazide: non-selective non-competitive antagonist

References

External links

* * {{Metabotropic glutamate receptor modulators Metabotropic glutamate receptors