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Molecular mechanism may explain how fevers spark seizures

trigger convulsions in children," she said. "I have been curious about this mystery for years."

Kang came to Vanderbilt to work with Macdonald, internationally renowned for his research on epilepsy and GABA-A receptors, proteins on the surfaces of nerve cells that normally quiet the brain's excited chatter.

GABA-A receptors were long suspected to play a role in epilepsy because they are the major inhibitory receptors in the brain and might therefore dampen the hyperexcitability that characterizes seizures. Phenobarbital and other barbiturate drugs and anti-anxiety drugs like Valium exert their calming effects by enhancing the activity of GABA-A receptors.

Indeed, mutations in GABA-A receptors were linked to inherited forms of epilepsy beginning in 2001. Macdonald's group has been characterizing the functional defects of the mutant GABA-A receptors, offering insight into the mechanisms underlying those epilepsies.

One of the common features in the families with mutations in the GABA-A receptor gamma subunit -- one of several protein "parts" that come together to make a functional receptor -- is a history of febrile seizures.

Kang and Macdonald had already discovered that GABA-A receptors containing mutant gamma subunits were not as good at getting to the neuronal cell surface, and Kang wondered what would happen to these receptors when they were exposed to high temperatures. She raised the temperature of cells expressing the mutant receptors to 40 degrees Celsius, simulating a "fever" of 104 degrees Fahrenheit, and she found that the receptors disappeared from the cell surface.

Fewer inhibitory GABA-A receptors on the cell membrane could leave a neuron open to the excitation and repetitive firing that characterizes seizures. The investigators are currently studying where the receptors go when the temperature is raised -- are they taken inside the cell more quickly, are they degraded, is their forward insertion in
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Source:Vanderbilt University Medical Center


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