Receiving and responding to extracellular messages is critical to the proper function of the nervous system. Glutamate is the major excitory neurotransmitter of the CNS, and metabotropic glutamate receptor 5 will play a major role in glutamate signaling. Metabotropic glutamate receptor 5 transmembrane domain is a homodimeric GPCR that resides in the cellular membrane [1]. This domain is a member of the Class C GPCR family and can further be categorized into the Group I subgroup. The transmembrane domain will signal through a Gq/11 pathway. mGlu5 will bind glutamate to the extracellular Venus flytrap domain and the signal will be transduced across the membrane to a heterotrimeric G protein, which will ultimately lead to calcium release and activation of PKC. This will elicit a excitory post-synaptic repose and modulate long term potentiation. Human metabotropic glutamate receptor 5 is found throughout the central nervous system. Areas containing high concentrations of this protein are often involved involved in emotions and higher cognition[2]. The localization of mGlu5 in the CNS and the presence of multiple domains makes mGlu5 a possible target for treating schizophrenia,Fragile X, depression, anxiety,and Alzheimer's disease[3].
[1]
Structure
Cross section view of mavoglurant in the binding pocket
Extracellular Domain
This is the shows the extracellular loops (ECL) 1, 2, and 3 highlighted in purple. Additionally in the ECL domain, a is attached to Helix 3 and the Amino Acid chain between Helix 5 and the N terminus. The disulfide bond is highlighted in yellow, and it is conserved in all classes of glutamate receptor 5 transmembrane domains.
Binding Pocket
Cross section view of mavoglurant in the binding pocket
In the 7 transmembrane domain (TMD), is in the 7TM domain pocket. Also, the lysozyme is attached to the intercellular region of the TMD.
The variation can be seen in positioning of alpha helices. Class C has seemingly less space for mavoglurant to enter compared to Class A and F (Wu). The binding of mavoglurant is seen to be varied in different locations due to helix position (Dore).
Function and Pathway
It all begins with glutamate binding to the venus fly trap domain. The signal transduction goes across the cystine-rich domain to the TMD. Next the dimerization of the TMD occurs. This activates the Gq/11 pathway, which activates phspholipase Cβ. The active phospholipase Cβ performs hydrolysis on phosphotinositides and generates inositol 1,4,5-trisphosphate and diacyl-glycerol. This results in calcium mobilization and activation of protein kinase C. (Niswender, Colleen M..(2010). "Metabotropic Glutamate Receptors: Physiology, Pharmacology, and Disease." Annu. Rev. Pharmacol. Toxicol. Annual Review of Pharmacology and Toxicology 50.1: 295-322.)
Disease
Parkinson's
Receiving and responding to extracellular messages is critical to the proper function of the nervous system. Glutamate is the major excitory neurotransmitter of the CNS, and metabotropic glutamate receptor 5 will play a major role in glutamate signaling. Metabotropic glutamate receptor 5 transmembrane domain is a homodimeric GPCR that resides in the cellular membrane [1]. This domain is a member of the Class C GPCR family and can further be categorized into the Group I subgroup. The transmembrane domain will signal through a Gq/11 pathway. mGlu5 will bind glutamate to the extracellular Venus flytrap domain and the signal will be transduced across the membrane to a heterotrimeric G protein, which will ultimately lead to calcium release and activation of PKC. This will elicit a excitory post-synaptic repose and modulate long term potentiation. Human metabotropic glutamate receptor 5 is found throughout the central nervous system. Areas containing high concentrations of this protein are often involved involved in emotions and higher cognition[3]. The localization of mGlu5 in the CNS and the presence of multiple domains makes mGlu5 a possible target for treating schizophrenia, Fragile X, depression, anxiety,and Alzheimer's disease[3].
