Brief Communication The GABAA Receptor 2 Subunit R43Q Mutation Linked to Childhood Absence Epilepsy and Febrile Seizures Causes Retention of 1 2 2S Receptors in the Endoplasmic Reticulum

The GABAA receptor 2 subunit mutation R43Q is an autosomal dominant mutation associated with childhood absence epilepsy and febrile seizures. Previously, we demonstrated that homozygous 1 3 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 1 2 2S(R43Q) GABAA receptor current amplitudes were reduced when receptors were assembled from coexpressed 1, 2, and 2S subunits and from 21 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 1 2 2S(R43Q) receptors had reduced surface expression. These results provide evidence that the 2S(R43Q) mutation impaired GABAA receptor function by compromising receptor trafficking and reducing surface expression.