spinqualitylabelsall models Metabotropic Glutamate Receptor PDB:7epa Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Contents 1 Introduction 2 Structural Highlights 2.1 Domains 3 Conformational Changes

Introduction

Within the central nervous system (CNS), various membrane receptors exist to detect extracellular signaling molecules and communicate this information intracellularly. Found in eukaryotes and known for its seven transmembrane helices, G-protein coupled receptor (GPCR) are one type of membrane bound receptors with conserved intracellular signaling via heterotrimeric G-protein^[1]. The metabotropic glutamate receptor (mGlu), a Class C GPCR, is a receptor utilized in glutamate signaling- which is essential in synaptic plasticity as well as the development and repair of the CNS^[2]. These receptors are specifically found in the pre- and postsynaptic neurons of the CNS^[2]. Eight different mGlu subtypes exist which are divided into three groups (I, II, III)^[2]. While each mGlu has a slightly different function and location, the structures of the different mGlu subtypes are very similar (Table 1) ^[2]. For each group, binding of the neurotransmitter glutamate to the mGlu introduces a conformational change that can activate a G-protein^[2].

Table 1. Classification of mGlu Subtypes[2]
Group	mGlu Type	Location	Function
I	mGlu1 mGlu5	Postsynaptic neurons	Activates calcium channels Excites adenylyl cyclase
II	mGlu2 mGlu3	Presynaptic neurons	Activates potassium channels Inhibits calcium channels Inhibits adenylyl cyclase
III	mGlu4 mGlu6 mGlu7 mGlu8	Presynaptic neurons	Activates potassium channels Inhibits calcium channels Inhibits adenylyl cyclase

To activate the mGlu transformation, glutamate acts as the protein's main agonist. Glutamate is an acidic, polar amino acid (Figure 1). This agonist binds to the extracellular portion of the glutamate receptor causing the transmembrane spanning region of the homodimer to change conformationally. This change allows for the mGlu to bind to a G-protein. This binding allows for the activation of a G protein which initiates a signaling cascade within the cell that can ultimately lead to a difference in the synapse’s excitability^[3]. In mGlu, the binding affinity of glutamate is also controlled by the binding of either a positive (PAM) or negative (NAM) allosteric modulator to a binding pocket within the seven TMD^[4].

Structural Highlights

mGlu receptors are dimeric proteins consisting of an . While a heterodimer of different mGlu subtypes can form, only homodimeric receptors can become active^[3]. Both the alpha and beta chains are comprised of : the venus fly trap (VFT), cysteine rich domain (CRD), and the transmembrane domain (TMD).

Domains

: The extracellular location in which the two glutamate agonists bind is known as the VFT. This domain includes a disulfide bond between C121 of the alpha and beta chains. This is shifted down and undergoes an upon glutamate binding which stabilizes the (Figure 2) Glutamate binds within the through intermolecular forces, specifically hydrogen bonding, with R57, S143, S145, T168, and K377 of the VFT. This binding initiates a closed VFT conformation.

: The portion of the protomer that connects the VFT with the TMD is known as the CRD. Many are located in this region between cysteines. As the connecting segment of the protein, it is critical in transmitting the conformational change caused by the binding of glutamate to the TMD. The change resulting from the binding of glutamate in the VFT brings the cysteine-rich domains pf the alpha and beta chain together to alter the configuration of the the seven TMD helices through its interaction with the VFT extracellular loop 2 (ECL2) ^[3]. This is mediated through interactions with amino acids at the apex of the CRD (e.g. I ^[3].

: The TMD consists of that are responsible for G-protein interactions and are able to transmit the signal from ligand binding across a membrane. In the , the asymmetric conformation of the helices is mediated by the hydrophobicity of helix 3 and 4 ^[3]. This allows for a to form between the monomers. Along with the interaction of the CRD with the ECL2 of the TMD, an allosteric modulator must bind within the transmembrane helices to allow for the conformation of the helices to be altered. This conformation allows for an along helix 6 of both protomers ^[4]. The stabilization of this conformation also enables G protein coupling with ICL2, ICL3, TM Helix 3 and the C terminus ^[4] (Figure 4).

Conformational Changes

1. In its resting state, mGlu is in an . In this conformation, the receptor is considered open with an inter-lobe angle of 44°^[3]. The structure has two free glutamate binding sites in the VFT, the CRDs are separated, and the TMD is not interacting with a G protein^[3].

2. In the intermediate activation state, also known as the open-closed conformation, one glutamate is bound in one binding pocket of VFT. This single is still considered inactive as the receptor has not changed the conformations in the CRD and thus the TMD. With the same asymmetric transmembrane helices formation, a is still present and mGlu cannot interact with a G protein^[3].

3. A second glutamate then binds to the other of the VFT. Mediated by L639, F643, N735, W773, and F776, a (PAM) also binds within the seven TMD helices of the alpha chain ^[3]. This closed conformation of the VFT now has an inter-lobe angle of 25° is considered to be in the ^[3]. The binding of these ligands allows the CRDs to compact and come together. This transformation causes the TMD to form a separate, active asymmetric conformation with a between the chains^[3].

4. The crossover of the helices from the alpha and beta chains allows for intracellular loop 2 (ICL2) and the C-terminus to be properly ordered to interact with a single G protein^[3]. While hydrogen bonding is present between the C-terminus and alpha helix 5 of the G-protein, this coupling is primarily driven by the hydrophobic interactions in the interface with the ɑ5 helix of the G protein^[3](Figure 4). This