A collaborative research by scientists from the National Centre for Biological Sciences (NCBS), Bangalore, and the Institute of Functional Genomics, University of Montpellier, INSERM, CNRS, France, has recently solved the structures of the complex brain receptor — metabotropic glutamate receptor 5 (mGlu5). They describe the binding mode of small molecules known to increase receptor activity, paving the way for new avenues in drug design.
The brain is a marvel of complexity. Every day, billions of neurons communicate to execute various functions in the body. At the heart of this communication are membrane proteins including glutamate receptors that transmit the signal. Glutamate receptors are of two kinds — Metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors. mGluRs are dimeric G protein-coupled receptors (GPCRs) that mediate cellular responses to the neurotransmitter L‑glutamate.
mGluRs are involved in regulating higher-order brain functions such as memory and learning says Vinothkumar K Ragunath, Associate Professor at NCBS and a co-author of the recently published article in Nature Communications. He adds, “Understanding their structure and modulation could be a key to treating a range of neurological disorders.”
Ragunath explains that decoding the structure of mGlu was a critical step in the study. mGlu has eight subtypes, and the structure of subtype mGlu5 is studied in this collaborative study. A study started nearly a decade ago as a result of overlapping interests between Ragunath and G. Lebon. The team chose mGlu5 due to its vital role in different brain functions.
mGlu5 has a modular architecture, which can be divided into three parts (domains): the large extracellular domain, also called Venus-fly trap (VFT); the 7‑transmembrane domain (7TM), embedded within the membrane; and the cysteine-rich domain, which links the two. This architecture can be visualised in the electron micrographs.
L‑glutamate binds to the VFT triggering a conformational change that activates the receptor through the 7TM domain, allowing for downstream signalling. The interaction and activity of the receptor can be enhanced further by the use of small molecules, says Raghunath. These are called positive allosteric regulators (PAMs). Unlike traditional drugs that directly activate the receptor, some PAMs enhance the receptor’s response to its natural ligand (such as L‑glutamate), while other PAMs can activate the receptor by themselves. Imagine a set of LEGO blocks; the structure is stable, but when you add one final piece, it enhances the overall functionality. PAMs work similarly by stabilising and enhancing the receptor’s activity.
The study’s major goal was to identify the binding of PAM to the receptor and the conformational changes that mGlu5 undergoes with different ligands.
The researchers tested three distinct PAMs and analysed the structures of the receptor. PAM binding to the receptor shifts the receptor’s equilibrium into different conformations in the 7TM domain. This finding indicates that PAMs can fine-tune the receptor’s activity, allowing for more precise control over how the receptor responds to its natural neurotransmitter (L‑Glutamate).
By using different PAMs, the team was able to show how the binding of these molecules changes the receptor’s behaviour. Essentially, PAMs don’t just push the receptor into an “ON” state; they fine-tune its activity. These interactions will help scientists understand how to design drugs that can precisely regulate receptor function. He further adds, “With the advent of mGlu structures by cryoEM, now one can aim to design PAMs specifically for one isoform of mGlu”.
The potential applications of this research are vast, explains Aravind Penmatsa, Associate Professor at the Indian Institute of Science (IISc), Bangalore, an expert who was not part of the original research. Penmatsa further adds,
Allosteric modulation is a potential pharmacological strategy for therapy in diverse neurological disorders.
Metabotropic Glutamate 5 receptors are implicated in several neurological and psychiatric conditions, including Parkinson’s disease, schizophrenia, anxiety, and depression. Penmatsa finds the study exciting as it focuses on understanding the subtle differences in receptor behaviour when PAMs bind to it.
By shedding light on the conformational diversity of these receptors and how PAMs interact with them, scientists are opening new doors to drug development that could revolutionise the treatment of different brain disorders. Penmatsa, however, cautions that the study is still in its early stages in terms of clinical implications.