GRM4 Membrane Protein Introduction

Introduction of GRM4

GRM4 (mGluR4) is encoded by the GRM4 gene localized in human chromosome 6. It is classified into group III metabotropic glutamate receptors (mGluRs) based on sequence homology, G-protein-coupling profile and ligand specificity. mGluRs are members of class C of the G-protein coupled receptors and possess a seven-transmembrane-spanning domain and an extracellular domain which contains the glutamate binding site. GRM4 is very highly expressed in the cerebellum, with lower levels of expression in the hippocampus, basal ganglia, and olfactory bulb. GRM4 is predominantly expressed presynaptically. It is commonly coupled to second messenger pathway via Gα_i/o proteins that inhibit adenylylcyclase thus cAMP formation and protein kinase Aactivation in heterologous expression systems. Besides, the GRM4 receptor can also act by coupling to the Gα_q protein, thus activating the phospholipase C effector system and thus excitatory events.

Functions of GRM4 Membrane Protein

GRM4 has been genetically deleted in mice to study the function of this receptor. Mice lacking this receptor show impaired cerebellar synaptic plasticity and learning complicated motor tasks as well as enhanced spatial reversal learning performance. GRM4 has also been shown to modulate GABA(A) receptor-mediated seizure activity, and mGluR4^–/– mice also lack motor stimulatory effects induced by ethanol. Highly selective, either orthosteric or allosteric, ligands for this receptor targeting the GRM4 for the treatment of disorders of the central nervous system (CNS) aswell as immunological (neuroinflammation) and metabolic diseases (diabetes) have been developed in recent years. For example, a highly selective GRM4 positive allosteric regulator (PAM), PHCCC, potentiates GRM4 responses at the striatopallidal synapse, and intracerebroventricular injection of PHCCC, as well as several other mGluR4 PAMs, have antiparkinsonian effects in rodent models.

Applications of GRM4 Membrane Protein in Literature

1. Charvin D., et al. A Novel mglur4 compound alleviates motor symptoms in primate models of Parkinson's disease. Journal of the Neurological Sciences. 2017, 381: 97.
   
   

   This article assessed the potential of a novel mGluR4 positive allosteric modulator (PAM), foliglurax, as an anti-parkinsonian treatment in non-human primate (NHP) models. The results showed that foliglurax can alleviate the motor symptoms of PD and the motor complications induced by levodopa.

2. Zhou F., et al. Changes of mGluR4 and the effects of its specific agonist L-AP4 in a rodent model of diffuse brain injury. Journal of Clinical Neuroscience. 2003, 10(6): 684-688. PubMed ID: 14592619
   
   

   This article examined the changes of expression of mGluR4 after diffuse brain injury (DBI) and the role of its specific agonist L-AP4 in vivo. The results showed that DBI increased the expression of mGluR4 and L-AP4 could provide neuroprotective effects against the disease.

3. Isherwood S. N., et al. Selective and interactive effects of D₂ receptor antagonism and positive allosteric mGluR4 modulation on waiting for impulsivity. Neuropharmacology. 2017, 123: 249. PubMed ID: 28487067
   
   

   This article investigated the relationship between mGluR2 and D₂ receptor in the regulation and inhibitory control of behavior by testing the effects of a positive allosteric mGluR4 modulator, Cpd11, both alone and in combination with the D2 receptor antagonist eticlopride on impulsivity. Results showed that these two receptors play a cooperative role in modulating impulsive behavior.

4. Davis M. J., et al. Role of mGluR4 in acquisition of fear learning and memory. Neuropharmacology. 2013, 66(3): 365-372. PubMed ID: 22884897
   
   

   This study assessed the effects of modulating mGluR4 signaling on acquisition and extinction of conditioned fear using the specific orthosteric mGluR4 agonist LSP1-2111. The results supported a role for mGluR4 signaling in the acquisition of fear learning and memory.

5. Pitsch J., et al. Functional role of mGluR1 and mGluR4 in pilocarpine-induced temporal lobe epilepsy. Neurobiology of Disease. 2007, 26(3): 623-633. PubMed ID: 17446080
   
   

   This article demonstrated that both mGluR1 and mGluR4 were potential drug targets to interfere with the development of hippocampal damage and seizure activity in temporal lobe epilepsy.

GRM4 Preparation Options

Membrane proteins represent challenging targets for structural biology and drug discovery due to their hydrophobicity and reliance on a lipid bilayer environment for stability. As a leading provider of membrane protein preparation services, Creative Biolabs is proud to offer custom membrane proteins in different functional formats to assist our clients in their research and discovery projects. Please see Magic™ Membrane Protein Production Service for more information. Aided by our versatile Magic™ anti-membrane protein antibody discovery platform, we also provide customized anti-GRM4 antibody development services.

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