PUBLICATION HIGHLIGHT
Understanding how positive allosteric modulators regulate metabotropic glutamate receptors
This publication highlight is part of the SBGrid/Meharry Medical College Communities Project, focused on science education and demonstrating how structural biology and preclinical science connect to medicine.
G protein-coupled receptors (GPCRs) are a large family of proteins found in the cells of many organisms, including humans. They play a crucial role in transmitting signals from outside the cell to the inside, helping cells respond to their environment. GPCRs are embedded in the cell membrane, having part of the receptor outside the cell surface, in addition to functional parts located inside the cell. The part within the cell membrane is called the transmembrane domain. GPCRs detect signals from various molecules, such as hormones, neurotransmitters, or even external sensory stimuli like light or odors.
When a signaling molecule (also called a ligand) binds to the GPCR on the outside of the cell, there is a change in the receptor’s shape known as a conformational change. The conformational change activates a G protein on the inside of the cell, which is attached to the receptor. Once the G protein is activated, a series of events is triggered inside the cell. Depending on the type of G protein, it can activate or inhibit different proteins, such as enzymes or ion channels, which lead to a specific cellular response. GPCRs are involved in many physiological processes, such as vision, smell, taste, and the regulation of mood, immune function, and blood pressure. Because GPCRs are so important in various bodily functions, they are common drug targets. It’s estimated that about one-third of all modern medications work by interacting with GPCRs.
One specific GPCR important in brain function is the metabotropic glutamate receptor (mGluR). As the name suggests, mGluRs are activated by glutamate, which is the most abundant neurotransmitter in the brain. mGluRs play a key role in how brain cells communicate with each other. They help in processes like learning, memory, and mood regulation. More specifically, mGluRs help regulate the activity at synapses, which are the connections between brain cells (neurons). mGluRs are involved in synaptic neuromodulation, a process of adjusting or modifying how signals are transmitted between neurons, which influences how the brain processes information. Because of this relationship, mGluRs are the target for many drugs aimed at treating neurological disorders.
Like many other GPCRs, mGluRs can be targeted by drugs, either by orthosteric or allosteric modulation. Orthosteric modulators bind to the same site on the receptor as the ligand. This site is known as the ligand binding domain or LBD. Allosteric modulators bind to a different site than the ligand (allosteric site). Instead of competing for the same binding site on the receptor, as orthosteric modulators do, allosteric modulators can either enhance or reduce the effects of the primary ligand binding to the receptor. Modulators that enhance receptor activity are called positive allosteric modulators, or PAMs. Many studies have shown that PAMs could be potential treatments for many neuropsychiatric diseases, including schizophrenia, however there is much left to learn about the structural and functional effects PAMs have on mGLuRs.
A published paper by SBGrid member Joshua Levitz, from Weill Cornell Medicine, and colleagues titled Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization, focuses on how PAMs interact with the mGluRs. The authors were able to identify the specific binding sites on the mGluR where PAMs interact by using cryo-electron microscopy. Understanding and locating these binding sites on mGluRs helps clarify how PAMs can enhance or modify the receptor’s function. By using other functional assays, they also found that PAMs not only enhance receptor activation but also influence the process of receptor internalization. The process of internalization removes the receptor from the cell surface after it has been activated, which affects how long the receptor can continue to produce a signal. These findings suggest that PAMs can modulate the duration and intensity of signaling by altering the internalization process, providing a new layer of control over receptor activity. Together, this knowledge could be used to develop PAMs with specific effects, potentially leading to targeted therapies with fewer side effects.
Read more in Nature Communications.
By KeAndreya Morrison, Meharry Medical College
KeAndreya Morrison is a biomedical sciences Ph.D. Candidate at Meharry Medical College studying the relationship between host and pathogen through the lens of structural biology. KeAndreya is a Georgia native where she completed her bachelor’s degree in biology at Fort Valley State University in Fort Valley, GA.
