Metabotropic Glutamate Receptors Family: A Key of CNS Disorders

Metabotropic Glutamate Receptors Family

Metabotropic glutamate (mGlu) receptor-mediated cellular responses are shaped by receptor-receptor interaction mechanisms, and understanding these mechanisms may lead to the development of novel therapeutic approaches for illnesses of the central nervous system (CNS). Based on their G protein coupling and amino acid sequence, the eight subtypes that make up the mGlu receptor family are separated into three groups. Gq/11 is connected to Group I (mGlu1 and mGlu5) receptor subtypes, whose activation promotes the hydrolysis of polyphosphoinositide (PI), leading to the production of diacylglycerol and inositol-1,4,5-trisphosphate (IP3). Gi/o proteins are linked to group II (mGlu2, mGlu3) and group III (mGlu4, mGlu6, mGlu7, and mGlu8) subtypes, which impede adenylyl cyclase action to transmit a signal. Subtypes of mGlu receptors can form intragroup heterodimers or homodimers.

Fig.1. mGlu receptor families.¹

Potential Drugs of Metabotropic Glutamate Receptors

Abnormalities in the expression of metabotropic glutamate receptors can lead to disease since they are involved in a multitude of functions. mGluRs have the potential to treat some diseases. For instance, LY354740, a mGlu2/3 agonist, may be useful in the treatment of generalized anxiety disorder, according to a clinical trial. Group II metabotropic glutamate receptor agonists are also showing increasing evidence of potential utility in the management of schizophrenia. Many ligands have been created for the mGlu2/3 and mGlu5 receptors, two types of mGlu receptors. These ligands' physiological and pharmacological importance as well as potential therapeutic uses have been demonstrated by studies utilizing them.

Tab.1. Ligands of Metabotropic Glutamate Receptors.²

Metabotropic Glutamate Receptors Assays for CNS Disorders Drug Discovery

• mGlu1 receptors

The primary projection neurons of the cerebellar cortex, Purkinje cells, have high expression of mGlu1 receptors, which are essential for cerebellar function. The analogous mGlu5 receptor is first expressed by Purkinje cells shortly after birth, and as the cells develop, the mGlu1 receptor gradually takes its position. In cerebellar diseases, treatment intervention can target the connection between mGlu1 and GABAB receptors. Numerous pieces of evidence point to the malfunctioning of mGlu1 receptors in various spinocerebellar ataxias (SCAs). P-chloro-phenyl-GABA is a GABAB receptor agonist that is used in clinical settings as a central myorelaxant to treat spasticity that is linked to a variety of central nervous system illnesses, including multiple sclerosis. Maybe this medication can be repurposed to treat cerebellar diseases in conjunction with a mGlu1 PAM.

• mGlu2/3 receptors

The cerebral cortex's 5-HT2A serotonin receptor-mediated electrophysiological responses are inhibited when the mGlu2/3 receptor is activated. One of the things that made people interested in mGlu2 receptors as a potential treatment target for schizophrenia is this fact. There may be a close connection between schizophrenia and 5-HT2A receptors. Strong 5-HT2A receptor antagonists are included in all second-generation antipsychotic medications.

• mGlu5 receptors

In humans, medium spiny projection neurons of the direct and indirect routes of the basal ganglia motor circuits create over two million synapses with dopaminergic axons of the nigro-striatal system. D2 receptors, which are connected to Gi/o proteins, negatively regulate GABAergic projection neurons in the indirect pathway. In both normal and dopamine-depleted mice, the importance of the A2A-mGlu5 receptor connection in the regulation of motor behavior has been investigated. The presence of A2A receptors was necessary for the mGlu5 receptor antagonist MPEP to stimulate motor behavior, suggesting that pharmacological inhibition of both mGlu5 and A2A receptors could be beneficial.

• mGlu7 receptors

mGlu7 receptors can be physiologically active in the presence of another mGlu receptor subtype in a heteromeric receptor complex, or they can be activated by glutamate concentrations that are synaptic but not extrasynaptic. For instance, mGlu7 receptors and mGlu2 receptors, which are dominant in the dimeric interaction and G protein activation, may form heterodimers. Adrenergic receptors and mGlu7 receptors may interact intricately, and this interaction may have implications for the pathogenesis and management of mental illnesses.

Creative Biolabs' Products and Services of GPCRs and Metabotropic Glutamate Receptors Family

Creative Biolabs is always monitoring the development of membrane protein drug discovery to help quickly offer a wide array of GPCRs products and service to accelerate the development of antibodies and other therapeutics. We offer a wide drug discovery services of GPCRs, including GPCR Cell-based Drug Screening In Vitro Assay Development Services, GPCR Profiling Services with Various Panels and other customized GPCR assays. Our highly qualified scientists are convinced that they can offer the greatest services at the most affordable prices to both domestic and foreign clients. Please contact us for more information.

Metabotropic Glutamate GPCR Assays Learn more

GPCR Cell-based Drug Screening In Vitro Assay Development Services Learn more

GPCR Profiling Services with Various Panels Learn more

References

1. Julio-Pieper, Marcela, et al. "Exciting times beyond the brain: metabotropic glutamate receptors in peripheral and non-neural tissues." Pharmacological reviews 63.1 (2011): 35-58.
2. Yasuhara, Akito, and Shigeyuki Chaki. "Metabotropic glutamate receptors: potential drug targets for psychiatric disorders." The open medicinal chemistry journal 4 (2010): 20.