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The Journal of Neuroscience, October 6, 2004, 24(40):8672-8677; doi:10.1523/JNEUROSCI.2717-04.2004

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BRIEF COMMUNICATION
The GABAA Receptor {gamma}2 Subunit R43Q Mutation Linked to Childhood Absence Epilepsy and Febrile Seizures Causes Retention of {alpha}1{beta}2{gamma}2S Receptors in the Endoplasmic Reticulum

Jingqiong Kang1 and Robert L. Macdonald1,2,3

Departments of 1Neurology, 2Molecular Physiology and Biophysics, and 3Pharmacology, Vanderbilt University, Nashville, Tennessee 37212

The GABAA receptor {gamma}2 subunit mutation R43Q is an autosomal dominant mutation associated with childhood absence epilepsy and febrile seizures. Previously, we demonstrated that homozygous {alpha}1{beta}3{gamma}2L(R43Q) receptor whole-cell currents had reduced amplitude with unaltered time course, suggesting reduced cell surface expression of functional receptors. In human embryonic kidney 293-T cells, we demonstrate that both heterozygous and homozygous {alpha}1{beta}2{gamma}2S(R43Q) GABAA receptor current amplitudes were reduced when receptors were assembled from coexpressed {alpha}1, {beta}2, and {gamma}2S subunits and from {beta}2-{alpha}1 tandem subunits coexpressed with the {gamma}2L subunit. Using fluorescence confocal microscopy, we demonstrated that mutant receptors containing enhanced yellow fluorescent protein-tagged {gamma}2S subunits had reduced surface expression and were retained in the endoplasmic reticulum. In addition, using biotinylation of surface receptors and immunoblotting, we confirmed that {alpha}1{beta}2{gamma}2S(R43Q) receptors had reduced surface expression. These results provide evidence that the {gamma}2S(R43Q) mutation impaired GABAA receptor function by compromising receptor trafficking and reducing surface expression.

Key words: GABAA receptor; R43Q mutation; endoplasmic reticulum; receptor trafficking; childhood absence epilepsy; febrile seizures

Received March 13, 2004; revised August 23, 2004; accepted August 23, 2004.




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