Hopkins Scientists Identify Communications "Matchmaker"

March 20, 1997

HOPKINS SCIENTISTS IDENTIFY COMMUNICATIONS "MATCHMAKER"

Newly identified protein may help organize location of nerve cell message receptors

Johns Hopkins researchers have identified a protein that helps biochemical "ears" on the surface of brain cells line up close to the areas where nearby brain cells "speak."

The newly identified molecule, named glutamate receptor interacting protein or GRIP, appears to help structures known as neurotransmitter receptors cluster together on some brain cells directly across from the message-transmitting ends of other nerve cells.

"This protein has the potential to affect the ability of nerve cells to communicate and to play a role in learning and memory," says Richard Huganir, Ph.D., professor of molecular biology and genetics and Howard Hughes Medical Institute Investigator.

"This is still speculative, but GRIP might help gather receptors at a frequently used connection between two nerves, ensuring that messages get through more quickly and more strongly at that connection."

Huganir and other neuroscientists believe the brain "creates" memories by adjusting the ability of nerve cells to communicate with each other.

In a paper in this week's Nature, Huganir's team describes finding GRIP through study of the AMPA receptor, which is involved in the transmission of rapid or "excitatory" signals between brain cells. AMPA receptors vary in design, but normally one part of the receptor, called GluR2, is consistent. The lab looked for proteins that bind to the GluR2 c-terminus, a part that sticks down into the nerve cell.

"What we pulled out was GRIP, this very large protein with a unit in it that's repeated seven times," says Huganir. "The repeated unit is a PDZ domain, a new protein structure that's involved in many protein-protein interactions."

The fourth and fifth PDZ domains bind to the end of GluR2's c-terminus, so one GRIP protein may anchor two AMPA receptors.

To test GRIP's connection to receptor clustering, Huganir made nerve cells in culture dishes produce extra copies of the c-terminus. With the extra copies blocking GluR2's ability to bind with GRIP, normal clustering of AMPA receptors decreased dramatically.

Researchers are currently developing a mouse that lacks the gene for GRIP to further study the protein's role. Huganir is also eager to learn what proteins plug into GRIP's five remaining PDZ sockets. "These could be proteins that help message transmission, or they could be structural proteins inside the nerve cell," speculates Huganir.

Other authors on the paper were Hualing Dong, a Ph.D. candidate; Richard O'Brien, M.D.; Eric Fung, an M.D./Ph.D. candidate; Anthony Lanahan, Ph.D.; and Paul Worley, M.D.

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