The pharmaceutical industry has waited a long time to determine the structure of a protein that plays an important role in memory and in developing numerous physiological processes, including low blood pressure, low body temperature, obesity, analgesia, drug addiction, cancer-cell growth, Parkinson’s disease and schizophrenia. Now researchers have determined the structure.
What is metabotropic glutamate receptor 5 (mGluR5)? The pharmaceutical industry has long been waiting to determine the structure of this protein, which functions as a receptor in the membranes of brain cells and sends signals from the environment into the cells.
The reason for the great interest is that mGluR5 probably plays an important role in memory and in developing numerous physiological processes.
Pharmaceutical companies are now pleased that their development departments can start designing various drug candidates that can interact with this recently mapped protein.
“The protein is unbelievably interesting for the pharmaceutical industry, which has waited a long time to manufacture drugs that target the protein to counteract such disorders as obsessive-compulsive disorder and attention deficit hyperactivity disorder and other disorders associated with addiction or learning difficulties. These are some of the very promising targets for this type of medicine,” says a researcher involved in determining the structure of the protein, Rasmus Fonseca, Postdoctoral Fellow, Department of Structural Biology, Stanford University School of Medicine, Palo Alto, CA, USA.
The study has been published in Nature.
Protein functions like a transistor in a computer
MGluR5 is located in the cell membranes of neurons, which capture signals in the form of glutamate, a neurotransmitter that other neurons emit.
Glutamate acts as a signal transmitted from neuron to neuron, and the receptor is an important part of the wiring network needed to get the signal from one point to another in the nervous system.
MGluR5 is located on the cell surface, and part of it is shaped like a baseball glove that protrudes from the surfaces of neurons and captures glutamate from the surrounding environment. The other part of the receptor is anchored in the cell membrane and sends signals into the cell when the baseball glove has captured glutamate.
It is that simple.
“A receptor is like a transistor in a computer that regulates the current in the various components. Like a computer that does not work if the whole system has power all the time, the nervous system ceases to function if there is no mechanism to switch things off at various times. This is what these receptors do,” explains Rasmus Fonseca.
Receptor is essential for memory
MGluR5 is interesting because various studies on mice have shown that it plays an important role in many aspects of a well-functioning brain.
These experiments have shown that memory depends on these receptors.
When scientists send mice through a simple maze with a reward at the exit, the mice learn how to navigate the maze and take the direct route to the exit after 5–10 attempts. Thus, they remember how to navigate the maze.
However, if the researchers disable mGluR5, things go wrong and the mice cannot learn how to find their way through the maze and have to search for the correct route every time.
Their ability to remember is greatly reduced.
“We assume that this receptor plays a similar role in people’s memory and ability to store information. This may therefore be an interesting target for various types of medicine intended for memory or learning disorders,” says Rasmus Fonseca.
Mice without the receptor do not become addicted
Another experiment has shown that mGluR5 also plays an important role in addiction.
When researchers carried out experiments on mice that gave them a dose of morphine every time they placed their feet on a plate, the mice quickly became addicted to the morphine injections and ended up dying from an overdose.
Conversely, when the researchers removed mGluR5, the mice were no longer addicted to the morphine and had no interest in getting up on the plate.
“This is very interesting in relation to people. For example, imagine taking very strong painkillers to manage extreme pain, which would normally be addictive. If the receptor can be silenced, people may be able to avoid the subsequent addiction. These people may also not remember much of what has happened, which could certainly be a benefit if they have had extensive pharmaceutical treatment,” explains Rasmus Fonseca.
Various advanced techniques used
The researchers mapped the structure of mGluR5 using several techniques.
They used X-ray crystallography: first crystallizing the protein, then freezing it and sending X-rays through it. The researchers can use the scattering of the X-rays to determine the structure of the protein.
However, this part of the mapping works best for the part of a membrane protein that protrudes from the membrane; the part of the protein embedded in the membrane itself is more difficult to crystallize since it is located in a fat layer.
To map this section of the protein, the researchers used another technique called cryoelectron microscopy, taking several hundred images of the protein with an electron microscope.
Each image is indistinct and not useful, but the researchers can use advanced imaging software to consolidate the hundreds of images into one sharp image that shows the structure of the membrane-bound part of the protein.
“In addition, we have mapped the structure of the protein when it is bound to glutamate and other molecules. We now have an overview of the protein’s structure in various conformations that pharmaceutical companies can use to create preliminary computer simulations of substances that potentially interact with mGluR5,” says Rasmus Fonseca.
“Conformational transitions of a neurotensin receptor 1–Gi1 complex” has been published in Nature. In 2015, the Novo Nordisk Foundation awarded a Visiting Scholar Fellowship at Stanford Bio-X to co-author Rasmus Fonseca, who spent 3 years at Stanford Bio-X followed by a year at the University of Copenhagen.