The brain functions by processing electrical and chemical signals, thanks to the presence of brain cells: neurons, the primary functional units, and glial cells, which provide support to neurons. For these connections to function properly, brain cells rely on cell surface proteins that act as receptors to external stimuli, facilitating communication between neurons at junctions called synapses.
In this context, metabotropic glutamate (mGlu) receptors are membrane proteins widely expressed in the human brain. Their main role is to modulate synaptic transmission, and they have been implicated in diseases such as Alzheimer’s disease, schizophrenia, and Parkinson’s disease. However, to date, no drugs targeting these receptors are available on the market to treat neurological diseases—primarily due to limited efficacy observed in clinical trials.
One possible explanation is the dynamic nature of mGlu receptors. Although they are classified as cell surface proteins, they are highly mobile and can translocate inside the cell—a process known as internalization—in response to stimuli. This behaviour can affect their availability at the cell surface and, consequently, their response to drugs. This is particularly relevant for chronic neurological disorders, where sustained drug action is often required.
Despite over 30 years of research on mGlu receptors, their internalization properties have remained poorly understood. Do mGlu receptors internalize in response to stimuli in brain cells? If so, which stimuli? What cellular machinery do they use to internalize?
Answering these questions is critical for designing more effective drugs that can target mGlu receptors in chronic brain diseases.
GLUGLU aimed to address these questions by combining two cutting-edge techniques mastered by the host team: nanobodies and time-resolved Förster Resonance Energy Transfer (TR-FRET).First, nanobodies are antibody fragments derived from camelids. Due to their small size, they can access tight spaces and selectively bind to a specific protein—or even to a specific conformation of a protein. Second, TR-FRET is based on the transfer of energy between two fluorescent molecules when they are in close proximity.
Thanks to the use of selective nanobodies for mGlu receptors tagged with FRET-compatible fluorophores, GLUGLU revealed for the first time how mGlu receptors are internalized in brain cells, as well as the pathways involved. By uncovering the internalization mechanisms of mGlu receptors for the first time, GLUGLU addresses a relevant barrier in the design of effective and long-lasting brain-targeted therapies.
