UIC researchers show protein routes messages in nerve cells

Nerve cells relay messages at blink-of-the-eye speeds by squirting chemicals called neurotransmitters across tiny gaps called synapses to awaiting message receptors. But lots of different receptors and neurotransmitters work simultaneously. Which goes where to send the proper message?

Research reported in the July 20 issue of the Journal of Neuroscience (released online July 13) by a team led by David Featherstone, a University of Illinois at Chicago assistant professor of biology, provides some important preliminary answers.

Featherstone and UIC post-doctoral associate Kaiyun Chen, along with German researchers Carlos Merino and Stephan Sigrist at the European Neuroscience Institute in Goettingen, chose the common fruit fly as their research animal and the chemical glutamate — present in fruit flies and humans — as their neurotransmitter of choice.

“It’s still unknown how glutamate receptors get to precisely where they’re supposed to go on a cell in order to mediate the neurotransmission,” said Featherstone. “If the receptors are not in the right place, then the message becomes less efficient. Or if receptors are the wrong type, the message could get completely mixed up.”

Such mix-ups can lead to a condition called synaesthesia, where, for example, a sound may have taste, or an image may have a smell. The molecular basis of this condition remains unknown.

“It all comes down to the receptors being in the right place at the right time,” said Featherstone. “So our question was, how do these receptors know where they’re supposed to go at the time they’re supposed to be there?”

Fruit flies proved to be ideal test animals for answering the question because a synapse called the neuromuscular junction in the fly works much like synapses in human brain cells.

“We can quickly mutate the flies,” said Featherstone. “We looked among thousands of them for those without the glutamate receptors in the right place at the right time. Then we knew that the gene we mutated codes for a protein that is critical for getting those receptors to the right place at the right time.”

Featherstone and his colleagues found that a protein called coracle — known as 4.1 in humans — links receptors on a nerve cell’s membrane to its internal structure, or cytoskeleton. Because 4.1 only interacts with certain receptor proteins, it functions as a sorting agent to ensure that only the correct type of receptor gets attached.

The work by the researchers also identifies the cytoskeleton proteins to which the receptors are tied: actin.

“Many researchers have identified proteins that interact with glutamate receptors, but there’s never previously been a link found to the cytoskeleton,” said Featherstone. “This work finally ties the receptors to the cell framework to provide a complete picture.”

Confirmation of these mechanisms in a mammal such as a mouse or a rat can help researchers understand how nerves need to be reconnected after spinal cord injury, or may open doors to developing drugs that can manipulate proteins that cause neurological diseases in humans.