Metabotropic glutamate receptor

Type of glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G protein coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

The mGluRs perform a variety of functions in the central and peripheral nervous systems: For example, they are involved in learning, memory, anxiety, and the perception of pain. They are found in pre and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. Like other metabotropic receptors, mGluRs have seven transmembrane domains that span the cell membrane. Unlike ionotropic receptors, metabotropic glutamate receptors are not ion channels. Instead, they activate biochemical cascades, leading to the modification of other proteins, such as ion channels. This can lead to changes in the synapse's excitability, for example by presynaptic inhibition of neurotransmission, or modulation and even induction of postsynaptic responses. A dimeric organization of mGluRs is required for signaling induced by agonists.

The receptors in group II, including mGluRs 2 and 3, and group III, including mGluRs 4, 6, 7, and 8, (with some exceptions) prevent the formation of cyclic adenosine monophosphate, or cAMP, by activating a G protein that inhibits the enzyme adenylyl cyclase, which forms cAMP from ATP. These receptors are involved in presynaptic inhibition, RO4491533 acts as a negative allosteric modulator of mGluR2 and mGluR3.

Different types of mGluRs are distributed differently in cells. For example, one study found that Group I mGluRs are located mostly on postsynaptic parts of cells, while groups II and III are mostly located on presynaptic elements, All mGluRs except mGluR6 are thought to exist in the hippocampus and entorhinal cortex. a type of ion channel linked receptor that is central in a neurotoxic process called excitotoxicity. Proteins called PDZ proteins frequently anchor mGluRs near enough to NMDARs to modulate their activity. It has been suggested that mGluRs may act as regulators of neurons' vulnerability to excitotoxicity (a deadly neurochemical process involving glutamate receptor overactivation) through their modulation of NMDARs, the receptor most involved in that process. Excessive amounts of N methyl D aspartate (NMDA), the selective specific agonist of NMDARs, has been found to cause more damage to neurons in the presence of group I mGluR agonists. On the other hand, agonists of group II and III mGluRs reduce NMDAR activity. Group II and III possibly by reducing the activity of NMDARs. Metabotropic glutamate receptors are also thought to affect dopaminergic and adrenergic neurotransmission.

The first demonstration that glutamate could induce the formation of molecules belonging to a major second messenger system was in 1985, when it was shown that it could stimulate the formation of inositol phosphates. This finding allowed in 1987 to yield an explanation for oscillatory ionic glutamate responses and to provide further evidence for the existence of metabotropic glutamate receptors. In 1991 the first metabotropic glutamate receptor of the seven transmembrane domain family was cloned. More recent reports on ionotropic glutamate receptors able to couple to metabotropic transduction systems suggest that metabotropic responses of glutamate might not be limited to seven transmembrane domain metabotropic glutamate receptors.