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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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The GABA_A Receptor 2 Subunit R43Q Mutation Linked to Childhood Absence Epilepsy and Febrile Seizures Causes Retention of 122S Receptors in the Endoplasmic Reticulum

Jingqiong Kang¹ and Robert L. Macdonald^1,2,3

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

The GABA_A receptor 2 subunit mutation R43Q is an autosomal dominant mutation associated with childhood absence epilepsy and febrile seizures. Previously, we demonstrated that homozygous 132L(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 122S(R43Q) GABA_A receptor current amplitudes were reduced when receptors were assembled from coexpressed 1, 2, and 2S subunits and from 2-1 tandem subunits coexpressed with the 2L subunit. Using fluorescence confocal microscopy, we demonstrated that mutant receptors containing enhanced yellow fluorescent protein-tagged 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 122S(R43Q) receptors had reduced surface expression. These results provide evidence that the 2S(R43Q) mutation impaired GABA_A receptor function by compromising receptor trafficking and reducing surface expression.

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

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

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