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Introduction

Metabotropic glutamate receptors are found in the central nervous system and play a critical role in modulating cell excitability and synaptic transmission^[1]. Glutamate is the main neurotransmitter in the brain and activates 8 different types of metabotropic glutamate receptors^[2]. Metabotropic Glutamate Receptor 2(mGlu2) is a member of the Class C GPCRFamily and can further be classified into the Group II subgroup of metabotropic receptors. Since mGlu2 is a part of the Class C GPCR family, it undergoes small conformational changes to the transmembrane domain (TMD) to move from the inactive to the fully active structure^[1]. Functionality of mGlu2 will be dependent on the concentration of glutamate. Higher concentrations of glutamate will promote stronger signal transduction from the extracellular domain to the transmembrane domain.

mGlu2 plays vital roles in memory formation, pain management, and addiction, which makes it an important drug target for Parkinson’s Disease^[3], Schizophrenia (blue link), Cocaine Addiction^[4], and many other neurological conditions.

Structure

Overall Structure

Cryo-EM studies of mGlu2 have yielded adequate structures that have acted as maps to aid in producing a better structural understanding of the inactive and active states of mGlu2^[1]. The overall structure of the mGlu2 is composed of 3 main parts: a ligand binding Venus FlyTrap Domain(VFT), followed by a Cysteine Rich Domain linker to the Transmembrane Domain that contains 7 alpha helices (7TM) on both the that aid in the binding of the G-Protein. Class C CPCRs such as mGlu2, are activated by their ability to form dimers. MGlu2 is a homodimer which is imperative to the receptor’s ability to relay signals induced by glutamate from the extracellular domain(ECD) to its transmembrane domain(TMD). The homodimer of mGlu2 contains an alpha chain and a beta chain. Occupation of both ECDs with the agonist, glutamate, is necessary for a fully active mGlu2^[5]. However, only one chain in the dimer is responsible for activation of the G-protein, this suggests an asymmetrical signal transduction mechanism for mGlu2^[1].

Inactive State

A few hallmarks of the inactive structure of mGlu2 are the Venus FlyTrap Domain in the open conformation, well separated Cysteine-Rich Domains, and distinct orientation of the 7 Transmembrane Domains (7TM). Perhaps the most critical component of the inactive form is the asymmetric TM3-TM4 interface formed by both of the 7 alpha helices in the alpha and beta chains in the transmembrane domain. The transmembrane domain is mediated mainly by helix IV on the alpha chain and helix lll on the beta chain of the dimer through hydrophobic interactions. These hydrophobic interactions between both transmembrane helices stabilize inactive conformation of mGlu2^[1].

Intermediate Form

Although there are no Cryo-EM images of the intermediate form, it is still a very important state that mGlu2 goes through. The agonist binding site is formed by both lobes of the Venus FlyTrap Domain. The receptor will remain in this inactive state if there are insufficient concentrations of glutamate available^[5]. Since glutamate is the main excitatory neurotransmitter in the central nervous system, its ability to bind is extremely important, especially for cell excitability.

PAM Bound Form

Figure 3:This is PAM located in its binding pocket. PAM, JNJ-40411813, is shown in magenta and colored by atom. The image shows four labelled alpha helices (III, V, VI, and VII) that create the binding pocket in the 7TM region of mGlu2 for PAM to bind within. The binding of PAM promotes the function of the mGLu2.

NAM Bound Form

Active State

Function

Clinical Relevance