A new method for studying the role of a critical neurotransmitter in disorders such as epilepsy, anxiety, insomnia, depression, schizophrenia, and alcohol addiction could help create safer and more efficient drugs for treating those conditions.
Gong Chen Lab
An illustration shows model synapses (resembling pink shower heads) sending GABA neurotransmitter signals between HEK (kidney) cells in order to test GABA-A receptor behavior. Differences in behavior can be especially important in predicting the side effects of GABA-receptor-targeting drugs such as Valium and Xanax.
Neurotransmitters—chemicals sent by nerves to trigger other cells to change their electrical responses—interact with special receptors located on the cell’s outer membrane. These receptors form inside the cell, and then are transported to different locations on the membrane to await the arrival of neurotransmitters. Understanding how receptors work and how they move to various locations is a critical step toward the development of new drugs targeting diseases that affect brain chemistry.
In their study, Chen and his team focused on the GABA-A receptor that responds to the neurotransmitter GABA. “The GABA-A receptors are associated with various disorders in which nerve-cell excitability is altered, such as epilepsy and anxiety, and these receptors mediate major inhibition in the brain,” Chen explains.
Each GABA-A receptor protein is made up of five subunits. Chen and his team focused on a group of subunits called Alpha and how altering them might affect the GABA-A receptor's location on the cell membrane.
First, the team used molecular engineering techniques to develop a model synapse between a nerve cell and a special kind of kidney cell used widely in cell-biology research called an HEK cell. They then altered the Alpha subunits in the GABA-A receptors expressed in the kidney cell to test how a single variation might affect the receptor’s behavior.
They found that the receptors behaved very differently in response to the GABA neurotransmitter depending on which subunit they had.
Specifically, when a GABA-A receptor had an Alpha 2 subunit, the receptor tended to locate at the synaptic region on the cell membrane. However, when a GABA-A receptor had an Alpha 6 subunit, the receptor tended to migrate to a different area on the cell membrane called the extrasynaptic region.
Understanding such a difference in receptor behavior, Chen says, can be especially important in predicting what side effects a drug might cause. For example, GABA-receptor-targeting drugs such as Valium and Xanax, which are used to treat anxiety, appear to directly change the GABA neurotransmitter’s synaptic transmission, significantly altering nerve-cell activity and causing side effects such as confusion, agitation, and memory loss.
“If we imagine that a cell represents a big city, then the synaptic regions are major highways leading to the city,” Chen says. “There are serious side effects of disrupting those ‘major highways’ because brain function relies upon a delicate excitation-inhibition balance and breaking that balance will affect the output of neural circuits.”
By the same analogy, the extrasynaptic regions could be thought of as less-trafficked, but numerous, smaller roads, he says. “The idea is that if drugs could be developed that manipulate only the extrasynaptic receptors rather than the synaptic receptors, the ’major highways’ would remain undisturbed and the heavy traffic could continue with less interruption.“
That could be a route toward creating new drugs with fewer side effects.
Gong Chen, Ph.D., is an associate professor of biology, guc2@psu.edu. In addition to Chen, other researchers who contributed to this study include Xia Wu, Zheng Wu, Gang Ning, Yao Guo, and Bernhard Luscher from Penn State; Rashid Ali and Angel L. De Blas from the University of Connecticut; and Robert L. Macdonald from Vanderbilt University.
The research is supported by two organizations of the U.S. National Institutes of Health: the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health. This work was published in the Journal of Biological Chemistry on Aug. 10.