NIH Scientists Use Subcellular Imaging to Visualize Structures of Brain Receptors
By C. Rajan, contributing writer
Researchers at the National Institutes of Health (NIH) have created high-resolution images of the glutamate receptor, a key protein involved in nerve signaling. The study was published online in the journal Nature on August 3, 2014.
Defects in protein based receptors are associated with various diseases, such as cancer, Alzheimer's disease, and schizophrenia. Visualizing the structure and shape of these cell receptors may enable scientists to design therapies that target them.
The research team was led by Sriram Subramaniam, Ph.D., National Cancer Institute (NCI), in collaboration with colleagues at NIH, including Mark Mayer, Ph.D., National Institute of Child Health and Human Development (NICHD), and collaborators at FEI, a company in Oregon that develops electron microscope technology.
To visualize the protein structures in various states, scientists used an imaging technique called cryo-electron microscopy (cryo-EM), which is a more versatile technique than the commonly used X-ray crystallography for studying protein shapes.
Glutamate receptors are located in nerve cell membranes and are involved in various functions in the nervous system, including memory. Defects and dysfunction in glutamate receptors are known to occur in several neurodegenerative and psychiatric disorders, including Parkinson's disease and depression, as well as some types of cancer.
The glutamate receptor serves as a channel to allow essential ions into the nerve cell, which induces nerves to send signals. It changes its conformation or shape from a closed to an open state to allow the passage of ions, and then changes back to closed state. The cryo-EM method captures the images of glutamate receptor in these different states, which can be used to derive the molecular movements involved.
Understanding how the ion channels operate could lead to the creation of medications that inhibit or enhance these receptor movements. "Seeing the actual receptor in high resolution is half the battle," Mayer said.
Subramaniam and his team have also recently used cryo-EM to visualize the structure of the enzyme beta-galactosidase, as reported in the Proceedings of the National Academy of Sciences on July 28, 2014. "We are now poised to analyze structures of a wide variety of biologically and medically relevant multi-protein complexes and membrane protein assemblies, which have historically represented the most challenging frontier in structural biology," said Subramaniam.