June 9, 2014

Structure of Receptor Involved in Brain Disorders

NMDA receptor. The NMDA receptor is a massive multi-subunit complex that looks like a hot air balloon. The upper, balloon-like portion is found outside the cell and responds to chemical messengers. The lower portion, the basket of the hot air balloon, is embedded in the cell membrane. Image courtesy of the researchers.

Scientists determined the structure of the intact NMDA receptor, an ion channel involved in many brain-related illnesses including Alzheimer’s disease, depression, schizophrenia, and autism. The finding may aid in the development of future therapies.

Nerve cells relay information between each other through specialized connections known as synapses. Synapses contain numerous proteins that help regulate message transmission. One key protein structure is a channel in the nerve cell surface called the NMDA (N-methyl, D-aspartate) receptor. It regulates the flow of ions into the cell, in turn triggering numerous biochemical processes.

Activation of the NMDA receptor is thought to play a role in learning and memory. Too much or too little activation of the NMDA receptor channel has also been linked to several neurological and psychiatric disorders.

The NMDA ion channel receptor is made up of 4 separate subunits, with 2 each of 2 different subunits. The structures of parts of these subunits are known. Drs. Erkan Karakas and Hiro Furukawa at Cold Spring Harbor Laboratory set out to determine the structure of the assembled NMDA receptor ion channel in order to better understand how the receptor functions. The work was funded in part by NIH’s National Institute of Mental Health (NIMH). Results appeared in the May 30, 2014, issue of Science.

The researchers made NMDA receptors in insect cells and then purified them. They crystallized the receptors in the presence of various chemicals that turn the channel on or off. Using X-ray crystallography, they were able to resolve the structure of the complete protein. By forming crosslinks between the 4 subunits to further stabilize the structure, they resolved it in even greater detail.

They found that the receptor is shaped like a hot air balloon. The basket part corresponds to the transmembrane domain—the part that goes through the cell membrane. This forms a gated channel, allowing ions—such as calcium—to enter the nerve cell. The balloon part of the receptor complex is located outside the cell. This area is where chemicals, known as neurotransmitters, bind to the receptor to turn it on or off.

The scientists further examined how the subunits fit together, and where molecules bind to trigger the channel to open or close. They compared the structure to those of similar types of ion channel receptors to better understand its function and regulation.

“Previously, our group and others have crystallized individual subunits of the receptor—just fragments—but that simply was not enough. To understand how this complex functions you need to see it all together, fully assembled,” Furukawa says. “Our structure defines the interfaces where multiple subunits and domains contact one another. In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”

—by Carol Torgan, Ph.D.

Related Links

References: Crystal structure of a heterotetrameric NMDA receptor ion channel. Karakas E, Furukawa H. Science. 2014 May 30;344(6187):992-7. doi: 10.1126/science.1251915. PMID: 24876489.

Funding: NIH’s National Institute of Mental Health (NIMH), Mirus Research Award, and the Robertson Research Fund of Cold Spring Harbor Laboratory.